WO2010077101A2 - Novel thiazolidinedione derivative and use thereof - Google Patents

Novel thiazolidinedione derivative and use thereof Download PDF

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Publication number
WO2010077101A2
WO2010077101A2 PCT/KR2009/007995 KR2009007995W WO2010077101A2 WO 2010077101 A2 WO2010077101 A2 WO 2010077101A2 KR 2009007995 W KR2009007995 W KR 2009007995W WO 2010077101 A2 WO2010077101 A2 WO 2010077101A2
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Prior art keywords
derivative
thiazolidine
dione
formula
mmol
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PCT/KR2009/007995
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French (fr)
Korean (ko)
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WO2010077101A4 (en
WO2010077101A3 (en
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조훈
무영
최철희
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조선대학교산학협력단
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Application filed by 조선대학교산학협력단 filed Critical 조선대학교산학협력단
Priority to KR1020117017782A priority Critical patent/KR101172638B1/en
Priority to EP09836422.7A priority patent/EP2383263B1/en
Priority to US13/142,924 priority patent/US8637558B2/en
Publication of WO2010077101A2 publication Critical patent/WO2010077101A2/en
Publication of WO2010077101A3 publication Critical patent/WO2010077101A3/en
Publication of WO2010077101A4 publication Critical patent/WO2010077101A4/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel thiazolidinedione derivatives and their use. More specifically, the present invention relates to novel thiazolidinedione derivatives and pharmaceutical compositions comprising the same.
  • Prostaglandin is a fatty acid derivative of 20 carbons and contains a ring of 5 carbons. The substance was discovered in 1935 by Swedish physiologist Wolf von Euler, who named it prostaglandin because he thought it was secreted from the prostate. It is presently widely present in the tissues of animals and is known to be quickly metabolized after synthesis from polyunsaturated fatty acids. These prostaglandins can stimulate smooth muscle contraction, depending on their form, and in some animals they act to lower or raise blood pressure, reduce or increase blood cohesion, as well as promote ion transport to the membrane, stimulate inflammation, and It is also known to act to inhibit vascular disease and viral infections.
  • Prostaglandins and their analogs are chemically unstable and have a short effective life due to rapid metabolism in vivo, which is why prostaglandins and their analogs generally have active sites in the form of hydroxyl and carboxyl groups. This is because enzymes rapidly inactivate these activators and are also present in molecular weights small enough to be easily removed and excreted from the body (Narumiya S. et al., 1999, Physiol. Rev. , 79 (4), 1193-). 1226).
  • prostaglandins and their homologues are chemically unstable and have very short effective periods, prostaglandins and their homologues have severe restrictions on their use for the treatment of diseases such as the respiratory system, genitals, nerves, endocrine glands and cardiovascular system.
  • Korean Patent No. 0598660 discloses the contents of 5 -thia- ⁇ -substituted phenyl-prostaglandin E derivatives that can strongly bind to the prostaglandin receptor for excellent activity
  • Korean Patent No. 0850133 No. discloses prostaglandin nitrooxy derivatives that reduce side effects caused by prostaglandins and maximize pharmacological effects
  • Korean Patent Laid-Open No. 2001-0023839 discloses aromatic C16-C20-substituted tetrahydropropanes useful as Fp agonists.
  • the other prostaglandin is disclosed.
  • prostaglandins have short physiological activity due to rapid metabolism in vivo.
  • the first step in this metabolic process is oxidation, where prostaglandins are NAD + dependent 15-hydroxyprostaglandin dehydrogenase (15-hydroxyprostaglandin dehydrogenase: 15-).
  • PGDH Endor, CM, & Tai, HH, 1995, J. Lipid Mediator Cell Signaling 12: 313-319.
  • 15-Hydroxyprostaglandin dehydrogenase is an enzyme that degrades prostaglandins, and the amount of prostaglandin is increased in tissues in which 15-PGDH is not expressed.
  • 15-PGDH enzyme is ubiquitous in mammalian tissue, initially extracted and isolated from placenta, lung and kidney (Krook M et al., 1990, Biochemistry , 29, 738-743), and its function is C Prostaglandin-based compounds containing a hydroxyl group (-OH) at the -15 position are oxidized to convert to 15-ketoprostaglandin and thus lose the biological activity of the compound (Tai HH et al., 2002, Adv). Exp Med Biol , 507, 245-250).
  • 15-PGDH plays a potential role in carcinogenesis, ie the expression of 15-PGDH is more pronounced in human prostate cancer cells than in cells treated with androgens. And increased expression of 15-PGDH in tumors from nude mice injected with human prostate cancer cells (M. Tong., 2000, Biochem. Biophys. Res. Commun ., 276, 77-81). ). Many researchers have anticipated that inhibiting or reducing the expression of 15-PGDH in cells can inhibit cancer development.
  • the present inventors found a new thiazolidinedione derivative while researching a new compound capable of inhibiting 15-PGDH in addition to the above compound, and the derivative not only has an excellent activity of inhibiting 15-PGDH, but also promotes hair growth.
  • the present invention was completed by confirming that there is an effect of improving cardiovascular disease, gastrointestinal disorder, bone formation effect, burn treatment effect and kidney disorder.
  • Another object of the present invention to provide a pharmaceutical composition for preventing hair loss and promoting hair growth containing the derivative as an active ingredient.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing the derivative as an active ingredient.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases containing the derivative as an active ingredient.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of kidney disease containing the derivative as an active ingredient.
  • Another object of the present invention to provide a composition for bone formation containing the derivative as an active ingredient.
  • Another object of the present invention to provide a composition for treating burns containing the derivative as an active ingredient.
  • the present invention provides a novel thiazolidinedione derivative.
  • the present invention also provides a pharmaceutical composition for preventing hair loss and promoting hair growth, containing the derivative as an active ingredient.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing the derivative as an active ingredient.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases containing the derivative as an active ingredient.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of kidney disease containing the derivative as an active ingredient.
  • the present invention also provides a composition for bone formation containing the derivative as an active ingredient.
  • the present invention provides a composition for treating burns containing the derivative as an active ingredient.
  • novel thiazolidinedione derivatives according to the present invention have an excellent effect of inhibiting 15-hydroxyprostaglandin dehydrogenase, it is possible to prevent and treat cardiovascular diseases, gastrointestinal diseases and kidney diseases which may be induced by 15-PGDH. It is effective in preventing hair loss and promoting hair growth, and in promoting bone formation as well as treating the burn.
  • the present invention is characterized by providing a novel thiazolidinedione derivative represented by the following formula (1).
  • a and A ' are each independently O or S
  • R 1 is hydrogen or CH 2 CH 2 OH
  • R 2 , R 3 , R 4 and R 5 are each independently hydrogen, nitro group, amine, Alkoxy, alkyl, trifluoromethyl, carboxyl, halogen or Can be,
  • R 6 is hydrogen, methyl, ethyl, substituted or unsubstituted (hetero) cycloalkyl, (hetero) cycloalkenyl or (hetero) aryl group; It may be selected from, dotted line represents a single or double bond, n may be an integer of 0 to 5.
  • R 3 In the case of R 2 , R 4 and R 5 are each independently H, NO 2 , NH 2 , CH 3 , Cl, Br, F, COOH, CF 3 , CH 3 O, CH 3 CH 2 O Can be selected, wherein R 4 is In the case of R 2 , R 3 and R 5 are each independently H, NO 2 , NH 2 , CH 3 , Cl, Br, F, COOH, CF 3 , CH 3 O, CH 3 CH 2 O Can be selected.
  • alkyl herein denotes an unsubstituted or substituted straight or branched chain hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
  • Representative unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like.
  • Substituted alkyl groups are halo, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, Sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkyloxy, guanidino, indolyl, imidazolyl, furyl, thienyl, thia Alkyl groups substituted by one or more selected from the group consisting of zolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl and morpholinyl, but are not limited to these.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkenyl refers to any of the above alkyl groups having two or more carbon atoms and comprising a double bond, preferably having two to four carbon atoms.
  • aryl denotes monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, for example phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each of which 1 to 4 substituents such as alkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, optionally substituted amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, carba Optionally substituted with moyl, alkylthioo, sulfonyl, sulfonamido, heterocyclyl and the like.
  • cycloalkyl denotes an optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon group having 3 to 12 carbon atoms, each of which is one or more substituents such as alkyl, halo, oxo, Hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl , Heterocyclyl, and the like.
  • Heterocyclo is a ring system that represents an optionally substituted fully saturated or unsaturated, aromatic or non-aromatic cyclic group, having at least one hetero atom in a ring containing at least one carbon atom.
  • Heterocyclic comprising heteroatoms
  • Each ring of the group may have one, two or three heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and the heterocyclic groups may be bonded to heteroatoms or carbon atoms.
  • thiazolidinedione derivative represented by Chemical Formula 1 may be derivatives prepared in Examples 1 to 130 of the present application.
  • the present invention provides a salt of a thiazolidinedione derivative represented by Chemical Formula 1, preferably a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts refer to salts suitable for use in contact with tissues of humans and lower animals without causing excessive toxicity, irritation and side effects within the scope of pure medical judgment. Such pharmaceutically acceptable salts are well known in the art (SM Berge et al ., 1977, J. Parmaceutical Sciences , 66: 1).
  • the salts can be prepared in situ during the final separation, purification and synthesis of the derivative compounds of the invention or separately by reaction with an inorganic base or an organic base.
  • the pharmaceutically acceptable salt when the derivative compound of the present invention contains an acidic group, it may form a salt with a base.
  • the salt examples include, but are not limited to, lithium salt, sodium salt or Salts with alkali metals such as potassium salts; Salts with alkaline earth metals such as barium or calcium; Salts with other metals such as magnesium salts; Organic base salts such as salts with dicyclohexylamine; Salts with basic amino acids such as lysine or arginine.
  • acid addition salts include, but are not limited to, inorganic acids, particularly hydrofluoric acid (for example, hydrofluoric acid and hydrobromic acid).
  • Hydroiodic acid or hydrochloric acid salts with nitric acid, carbonate, sulfuric acid or phosphoric acid; Salts with lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; Salts with benzenesulfonic acid or p-toluenesulfonic acid; Salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; And salts with amino acids such as glutamic acid or aspartic acid.
  • lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid
  • Salts with benzenesulfonic acid or p-toluenesulfonic acid Salts with organic carboxylic acids such as
  • the present invention may also include derivatives in the form of hydrates or solvates of the novel thiazolidinedione derivatives represented by Formula 1 (JM Keith, 2004, Trahedron Letters , 45 (13), 2739-2742). .
  • novel thiazolidinedione derivatives of Formula 1 according to the present invention may be isolated from nature or prepared by chemical synthesis of thiazolidinedione-based compounds known in the art.
  • the derivative compound according to the present invention is reacted by reacting the substituent compound to be substituted at 5 parts with an appropriate reaction solvent to obtain an intermediate product, and then reacting the intermediate product with 2,4-thiazolidinedione in an appropriate reaction solvent. It can manufacture.
  • the reaction solvent that can be used in the production process is not particularly limited as long as it is not involved in the reaction, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane; Halogenated hydrocarbons such as dichloromethane and chloroform; Amines such as pyridine, piperidine and triethylamine, acetone; Alkyl ketones such as methyl ethyl ketone and methyl isobutyl; Alcohols such as methanol, ethanol and propanol; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, hexamethyl phosphate triamide, and the like, and especially non-reactive used in organic synthesis.
  • ethers such as diethyl ether, tetrahydrofuran, dioxane
  • Halogenated hydrocarbons such as dichloromethane and
  • a solvent capable of separating the water generated during the reaction by the Dean-Stark trap is preferred.
  • examples of such a solvent include, but are not limited to, benzene, toluene, xylene, and the like.
  • Separation and purification of the reaction product is carried out through a process such as concentration, extraction, and the like, which is commonly performed in organic synthesis, and separation and purification may be performed through purification by column chromatography on silica gel, if necessary.
  • the invention also includes any modification to the methods for the preparation of novel thiazolidinedione derivatives, wherein the intermediate product obtainable at any stage thereof can be used as starting material for the remaining stages,
  • the starting material can be formed in the reaction system under reaction conditions, or the reaction components can be used in the form of its salts or optically enantiomers.
  • novel thiazolidine derivatives according to the invention are also possible isomers, such as substantially pure geometric (cis or trans) isomers, optical isomers, depending on the type of substituents used to prepare the derivatives, the intermediate product and the method of preparation. (Enantiomers) or racemates, all such possible isomers are included within the scope of the present invention.
  • novel thiazolidinedione derivative represented by the formula (1) according to the present invention is characterized by having an activity of inhibiting or inhibiting 15-hydroxy prostaglandin dehydrogenase (15-PGDH).
  • the present inventors have confirmed that the novel thiazolidinedione derivative of the present invention is an inhibitor of 15-PGDH, and the derivative of the present invention can be used for the prevention or treatment of diseases which may be caused by 15-PGDH. could be expected.
  • prostaglandins have been known to play an important role in hair growth, and in order to maintain or increase hair density, prostaglandins of various types (A 2 , F 2a , E 2 ) in various zones of the hair follicle or nearby skin environment are known.
  • a 2 , F 2a , E 2 has been found to be very essential.
  • enzymes that are specifically involved in the breakdown of prostaglandins are present in the dermal papilla of the hair, a critical area for hair survival, and 15-PGDH inactivates prostaglandins, especially PGF 2a and PGE 2 , damaging the scalp and causing hair loss.
  • Michelet JF et al., 2008, Exp. Dermatol , 17 (10), 821-8 Michelet JF et al., 2008, Exp. Dermatol , 17 (10), 821-8).
  • novel thiazolidinedione derivatives according to the present invention have an activity of inhibiting or inhibiting 15-hydroxy prostaglandin dehydrogenase (15-PGDH) that degrades prostaglandins, thereby improving scalp damage. It can prevent hair loss and has the effect of promoting hair growth.
  • 15-PGDH 15-hydroxy prostaglandin dehydrogenase
  • the present invention provides a pharmaceutical composition for preventing hair loss and promoting hair growth, which contains the novel thiazolidinedione derivative according to the present invention as an active ingredient.
  • alopecia refers to the entire hair follicle state with partial or general permanent hair loss, and the target of hair loss and hair growth may be human keratin fibers, in particular hair, eyebrows, eyelashes, beards, and mustaches. .
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing a novel thiazolidinedione derivative according to the present invention as an active ingredient.
  • Prostaglandins including the prostaglandin homologues produced in the body, are known to play a role in maintaining the proper functioning of the blood vessel wall, especially in the smooth muscle cell proliferation that relaxes blood vessels to prevent blood flow, prevents platelet aggregation, and surrounds the blood vessel wall. It is known to contribute to regulation (Yan. Cheng et al., 2006, J. Clin., Invest ). In addition, when the production of prostaglandins is inhibited or the activity is lost, degeneration of the lining of the blood vessel wall, aggregation of platelets and disruption of smooth muscle cells may be caused, leading to cardiovascular diseases, particularly in the case of high blood pressure. Prostaglandin production has been shown to be reduced (Tang EH, 2008, Cardiovasc Res ., 78 (1), 130-8).
  • novel derivative compounds according to the present invention have the activity of inhibiting or inhibiting 15-PGDH that degrades prostaglandins, prostaglandins (PGE 2 ) can be stored and activated in cells to prevent or treat cardiovascular diseases.
  • the cardiovascular disease is caused by degeneration of the lining of the blood vessel wall or abnormality in the regulation of platelet aggregation or smooth muscle cell function, low density lipoprotein cholesterol (hereinafter referred to as 'LDL-cholesterol'), cholesterol and
  • cardiovascular diseases include, but are not limited to, arteriosclerosis, hypertension, angina pectoris, hyperlipidemia, myocardial infarction and heart failure, including all diseases caused by hypercholesterolemia due to abnormally high triglycerides This includes.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases, which contains the novel thiazolidinedione derivative according to the present invention as an active ingredient.
  • Gastritis and gastric ulcers which are representative diseases of the gastrointestinal diseases, refer to a condition in which the gastrointestinal mucosa is digested by gastric acid to form ulcers.
  • gastric ulcer refers to a case of damage to the submucosal or muscular layer.
  • gastritis and gastric ulcers are not known to have a high degree of incidence, but are known to be caused only by an imbalance between attackers and defenders, that is, increase in attackers or weakening of defenders.
  • Factors that increase the attack factor include increased acid and pepsin secretion, and factors that weaken the protective factor include deficiency in the structure and form of the gastric mucosa, decreased mucus secretion, decreased bicarbonate ion secretion, and decreased prostaglandin production. Can be mentioned.
  • novel thiazolidinedione derivatives according to the present invention have an activity of inhibiting or inhibiting 15-PGDH that degrades prostaglandins that protect the gastric mucosa, thereby preventing or treating gastrointestinal diseases, especially gastritis and gastric ulcers. There is.
  • prostaglandins in the kidney are known to regulate blood flow in the kidney and to regulate urinary formation by both renal and vascular effects.
  • Clinical studies have shown that prostaglandin 1 (PGE 1 ) improves creatinine purification in patients with chronic kidney disease, prevents transplant rejection and cyclosporin toxicity in patients with kidney transplantation, rate of albumin excretion in urine in diabetic nephropathy, and N -acetyl- ⁇ - It has been shown to be effective in reducing D-glucosaminidase levels, and methods have been disclosed to prevent renal dysfunction by intravenous administration of prostaglandin compounds such as PGE 1 , PGE 2 and PGI 2 (Porter, Am). , 1989, J.
  • prostaglandins act as vasodilators that dilate blood vessels in the kidney and are known to cause renal failure when the production of prostaglandins in the kidney is inhibited (Hao. CM, 2008, Annu Rev Physiol, 70, 357-77). ).
  • novel thiazolidinedione derivative according to the present invention which inhibits or inhibits 15-PGDH that degrades prostaglandins can prevent or treat kidney disease due to renal dysfunction.
  • Renal dysfunction means that the normal creatinine is less than the purified amount, the normal free number is less than the purified amount, the level of normal blood urea or nitrogen or potassium or creatinine is higher than normal, or the kidney enzymes such as gamma glutamyl synthase, alanine force And the case where patidase, N -acetyl- ⁇ -D-glucosaminidase, or ⁇ -2-microglobulin has modulated activity, or macroalbuminuria exceeds normal levels.
  • the present invention provides a pharmaceutical composition for preventing or treating kidney disease, which contains a novel thiazolidinedione derivative according to the present invention as an active ingredient.
  • novel thiazolidinedione derivatives of the present invention are inhibitors of 15-PGDH, which can prevent hair loss and promote hair growth through the action of inhibiting the decomposition of prostaglandins, cardiovascular diseases, There is an effect that can treat or prevent gastrointestinal diseases and kidney diseases.
  • prostaglandins including PGE 1 , PGE 2 and PGF2a, have been found to stimulate bone resorption and bone formation to promote the action of increasing bone volume and strength (H. Kawaguchi et al., Clinical Orthop. Rel. Res ., 313, 1995, 36-46; J. Keller et al . , Eur. J. Exp. Musculoskeletal Res., 1, 1992, 8692).
  • 15-PGDH has the effect of inhibiting the activity of prostaglandins as described above.
  • novel thiazolidinedione derivatives according to the present invention may inhibit the activity of 15-PGDH and may have an effect of promoting bone resorption and bone formation.
  • the present invention can provide a composition for bone formation containing a novel thiazolidinedione derivative according to the present invention as an active ingredient.
  • novel thiazolidinedione derivatives according to the present invention have the effect of treating burns.
  • PGE 2 is known to act as a mediator for treating wounds or burns. Therefore, if 15-PGDH inhibits the activity of PGE 2 , which plays a role in treating wounds or burns, it may be possible to obtain a therapeutic effect by PGE 2 when a wound or burn occurs on the skin.
  • the novel thiazolidinedione derivatives according to the present invention have excellent activity of inhibiting 15-PGDH and thus can be used to treat wounds or burns, so the present invention is effective for the novel thiazolidinedione derivatives.
  • the composition for burn treatment containing as a component can be provided.
  • the inhibitor of 15-PGDH is a compound capable of inhibiting or reducing the activity of 15-PGDH enzyme, or inhibiting, decreasing or slowing the reaction catalyzed by the enzyme, particularly in humans. It means a derivative.
  • the pharmaceutical composition containing the derivative compound represented by Formula 1 according to the present invention as an active ingredient may be prepared by mixing with a pharmaceutically acceptable carrier or excipient or diluting with a diluent according to a conventional method.
  • the pharmaceutical composition may further include fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives.
  • the pharmaceutical compositions of the invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • compositions of the present invention may be prepared in various parenteral or oral dosage forms according to known methods.
  • excipients if necessary, binders and disintegrants in the derivative compounds of the present invention.
  • Lubricating agents, coloring agents, flavoring agents, and / or coagulants may be added and the resulting mixture may be prepared in the form of tablets, dragees, granules, powders or capsules by conventional methods.
  • the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, and the like.
  • Propanol, short syrup sucrose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate And polypyrrolidone.
  • the disintegrant include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monostearate and lactose.
  • the lubricant include refined talc, stearates, sodium borate, and polyethylene glycol.
  • the flavor include sucrose, beater orange oil, citric acid, and tartaric acid.
  • flavoring agents When preparing a solution for oral administration, flavoring agents, buffers, stabilizers, chemistries, etc. can be added to the compounds of the present invention, and can be prepared in the form of solvents, syrups or elixirs according to conventional methods.
  • buffers include sodium citrate
  • stabilizers include tragacanth, acacia and gelatin.
  • a pH adjusting agent, a buffer, a stabilizer, a relaxant, a local anesthetic may be added to the compound of the present invention, and the resultant mixture may be a subcutaneous injection, a muscle injection or an intravenous injection.
  • pH adjusters and buffers include sodium citrate, sodium acetate and sodium phosphate.
  • stabilizers include sodium pyrosulphite, EDTA, thioglycolic acid, and thioractic acid.
  • Local anesthetics include procaine hydrochloride and lidocaine hydrochloride, and examples of the relaxants include sodium chloride and glucose.
  • the compounds of the present invention may be formulated with pharmaceutically acceptable carriers known in the art, such as polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides, and, if desired, surfactants such as Tween. It can be added and prepared in the form of suppositories according to a conventional method.
  • a base When the ointment is prepared, a base, a stabilizer, a moisturizer, a preservative, or the like, which is usually used to prepare an ointment, may be added to the compound of the present invention, and the ointment may be prepared according to a conventional method.
  • the base include liquid paraffin, white waserine, pewter, octyldodecyl alcohol and paraffin
  • preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate and propyl paraoxybenzoate.
  • compositions formulated in various ways as described above may be administered in a pharmaceutically effective amount via a variety of routes including oral, transdermal, subcutaneous, intravenous or intramuscular.
  • the above pharmaceutically effective amount refers to an amount of a compound sufficient to improve or treat hair loss, cardiovascular disease, gastrointestinal disease and kidney disease, and the disease and its severity, age, weight, health condition, sex, and administration of the disease. Depending on the route and duration of treatment, it can be appropriately changed. Usually, it is administered at an effective dose of about 1 to 1000 mg for oral administration, about 0.1 to 500 mg for injection, and about 5 to 1000 mg for suppository. Can be.
  • the daily dosage of the formulation depends on the condition, weight, age and sex of the patient and cannot be determined in a batch. Usually the daily dosage is about 0.1-5000 mg, preferably about 1-1000 mg for adults. Administration can be repeated once or once several times a day.
  • Prostaglandins PGE 2
  • NAD + NAD +
  • NADH NAD +
  • Glutathione Sepharose 4B DTT
  • Sodium Dodecyl Sulfate SDS
  • EDTA EDTA
  • Reduced glutathione was purchased from Sigma, USA, and cDNA of human 15-PGDH was cloned from human placental cDNA library.
  • UV spectra was used a UV-VIS spectra photometer (Shimadzu Co., Ltd.)
  • NMR spectra was used JEOL JNM-LA 300 spectrometer (JEOL, Tokyo, Japan).
  • Derivative 1 represented by the following formula was prepared in the following manner.
  • Derivative 2 represented by the following formula was prepared by the following method.
  • Example 1 using the 4- (2- (morpholinoethoxy) benzaldehyde (1g, 4.3mmol) and 2,4-thiazolidinedione (504 mg, 4.3mmol) as an intermediate compound prepared by the method 5- (4- (2-morpholinoethoxy) benzylidene) thiazolidine-2,4-dione (5- (4) which is a derivative 2 represented by the above formula through a process of the second step of the derivative manufacturing process.
  • Derivative 3 represented by the following formula was prepared in the following manner.
  • the obtained compound was obtained in the same manner as in Example 2, except that instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step of the derivative manufacturing process, the derivative 3 of Formula 5 -(4- (2- (thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) was obtained.
  • Derivative 4 represented by the following formula was prepared by the following method.
  • the obtained compound was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used.
  • -[4- (2- (thiophen-3-yl) ethoxy) benzylidene] thiazolidine-2,4-dione (5- (4- (2- (Thiophen-3-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) was obtained.
  • Derivative 5 represented by the following formula was prepared by the following method.
  • Derivative 6 represented by the following formula was prepared by the following method.
  • Derivative 7 represented by the following formula was prepared in the following manner.
  • Derivative 7 represented by the following formula was prepared in the following manner.
  • Derivative 9 represented by the following formula was prepared by the following method.
  • the derivative 9 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1.
  • Phosphorus 5- (4- (2-cyclohexylethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione
  • Derivative 10 represented by the following formula was prepared in the following manner.
  • Derivative 11 represented by the following formula was prepared in the following manner.
  • Derivative 12 represented by the following formula was prepared in the following manner.
  • Derivative 13 represented by the following formula was prepared in the following manner.
  • Derivative 14 represented by the following formula was prepared in the following manner.
  • the derivative 14 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1.
  • Phosphorus 5- (4- (2- (piperidin-1-yl) ethoxy) benzylidene) thiazolidine-2,4-dione
  • 5- (4- (2- (Piperidin-1-yl) ethoxy ) benzylidene) thiazolidine-2,4-dione
  • Derivative 15 represented by the following formula was prepared in the following manner.
  • Derivative 16 represented by the following formula was prepared in the following manner.
  • Derivative 17 represented by the following formula was prepared in the following manner.
  • Derivative 18 represented by the following formula was prepared in the following manner.
  • Derivative 19 represented by the following formula was prepared in the following manner.
  • Derivative 20 represented by the following formula was prepared in the following manner.
  • Derivative 21 represented by the following formula was prepared in the following manner.
  • a derivative 21, dione was obtained.
  • Derivative 22 represented by the following formula was prepared in the following manner.
  • a derivative 22 was obtained, which was (4- (thiophen-2-ylmethoxy) thiazolidine-2,4-dione (5- (4- (Thiophen-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione)
  • the yield of the obtained derivative 22 is 94%
  • Derivative 23 represented by the following formula was prepared in the following manner.
  • Derivative 24 represented by the following formula was prepared in the following manner.
  • Derivative 25 represented by the following formula was prepared in the following manner.
  • Derivative 26 represented by the following formula was prepared in the following manner.
  • Derivative 27 represented by the following formula was prepared in the following manner.
  • Derivative 28 represented by the following formula was prepared in the following manner.
  • Derivative 29 represented by the following formula was prepared in the following manner.
  • Derivative 30 represented by the following formula was prepared in the following manner.
  • Derivative 31 represented by the following formula was prepared in the following manner.
  • Derivative 32 represented by the following formula was prepared in the following manner.
  • Derivative 33 represented by the following formula was prepared in the following manner.
  • Derivative 34 represented by the following formula was prepared in the following manner.
  • the derivative was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used.
  • Phosphorus 5- (2-chloro-3- (2-cyclohexylethoxy) benzylidene) thiazolidine-2, -4-dione (5- (2-Chloro-3- (2-cyclohexylethoxy) benzylidene) thiazolidine- 2,4-dione) was obtained.
  • Derivative 35 represented by the following formula was prepared in the following manner.
  • Derivative 36 represented by the following formula was prepared in the following manner.
  • Derivative 37 represented by the following formula was prepared in the following manner.
  • Derivative 38 represented by the following formula was prepared in the following manner.
  • Derivative 39 represented by the following formula was prepared in the following manner.
  • Derivative 40 represented by the following formula was prepared in the following manner.
  • Derivative 41 represented by the following formula was prepared in the following manner.
  • the derivative 41 represented by the above formula 5 -(4-ethoxybenzylidene) thiazolidine-2,4-dione (5- (4-Ethoxybenzylidene) thiazolidine-2,4-dione) was obtained. At this time, the yield of the derivative 41 was 91%.
  • Derivative 42 represented by the following formula was prepared in the following manner.
  • the intermediate product 4- (cyclohexylmethoxy) benzaldehyde was prepared in the same manner, except that cyclohexylmethanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. Obtained, wherein the yield of the intermediate product was 79%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used.
  • a derivative 42 was obtained, which is 4- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione).
  • Derivative 43 represented by the following formula was prepared in the following manner.
  • Derivative 44 represented by the following formula was prepared in the following manner.
  • the intermediate product 4- (benzyloxy) benzaldehyde was obtained by the same method except that benzyl alcohol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. The yield of this intermediate product was 92%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used.
  • a derivative 44 was obtained, which was (4- (benzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Benzyloxy) benzylidene) thiazolidine-2,4-dione).
  • Derivative 45 represented by the following formula was prepared in the following manner.
  • the intermediate product 4- (cyclohexyloxy) benzaldehyde was prepared in the same manner, except that cyclohexanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. Obtained, wherein the yield of the intermediate product was 94%. Thereafter, the derivative was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used.
  • Derivative 46 represented by the following formula was prepared in the following manner.
  • the intermediate product 4- (cyclohexylethyloxy) benzaldehyde was prepared in the same manner except that cyclohexylethanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. Obtained, wherein the yield of the intermediate product was 89%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used.
  • Phosphorus 5- (4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. .
  • Derivative 47 represented by the following formula was prepared in the following manner.
  • the intermediate product 4- (3- Cyclohexylpropoxy) benzaldehyde was obtained with a yield of 88% of the intermediate product. Thereafter, the derivative was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used.
  • Derivative 48 represented by the following formula was prepared in the following manner.
  • Derivative 49 represented by the following formula was prepared in the following manner.
  • Derivative 50 represented by the following formula was prepared in the following manner.
  • Derivative 51 represented by the following formula was prepared in the following manner.
  • Derivative 52 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (4- (2-cyclohexylpropoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylpropoxy) -3-methylbenzylidene) thiazolidine-2,4 -dione) was obtained. The yield was 89.1%.
  • Derivative 53 represented by the following formula was prepared in the following manner.
  • Example 51 In preparing the derivative of Example 51, 4-cyclohexyl-1-butanol (1 g, 6.4 mmol) was used instead of cyclohexane methanol, and 0.87 g of 4-hydroxy-3-methylbenzaldehyde was used. Using the same method, except that the amount was used, 1.43 g of the intermediate product 4- (2-cyclohexylbutoxy) -3-methylbenzaldehyde was obtained, and the yield of the intermediate product was 81%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • Derivative 54 represented by the following formula was prepared in the following manner.
  • Derivative 55 represented by the following formula was prepared in the following manner.
  • Derivative 56 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- [4- (2-phenylpropoxy) benzylidene] -1,3-thiazolidine-2,4-dione was obtained, and the yield was 80.1%.
  • Derivative 57 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- [4- (2-phenylbutoxy) benzylidene] -1,3-thiazolidine-2,4-dione was obtained, and the yield was 85%.
  • Derivative 58 represented by the following formula was prepared in the following manner.
  • Derivative 59 represented by the following formula was prepared in the following manner.
  • Derivative 60 represented by the following formula was prepared in the following manner.
  • Example 51 In preparing the derivative of Example 51, instead of cyclohexanemethanol, 1 g and 7.8 mmol of cyclohexaneethanol were used, and 2-methoxy-4-hydroxybenzaldehyde (1.19 g, 7.8 instead of 4-hydroxy-3-methylbenzaldehyde) was used. mmol), and the intermediate product 4- (2-cyclohexylethoxy) -2-methoxybenzaldehyde was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. g was obtained, wherein the yield of the intermediate product was 87.3%.
  • Derivative 61 represented by the following formula was prepared in the following manner.
  • Derivative 62 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- 4-((2,3-dihydrobenzo [b] [1,4] dioxin-2-yl) methoxy) benzylidene) thiazolidine-2,4-dione
  • 5- 4- ((2,3-Dihydrobenzo [b] [1,4] dioxin-2-yl) methoxy) benzylidene) thiazolidine-2,4-dione
  • (1.12 g, 82.4% yield) was obtained, and the compound of the derivative 62 was obtained.
  • Derivative 63 represented by the following formula was prepared in the following manner.
  • Example 51 In preparing the derivative of Example 51, 1 g, 8.8 mmol of cyclohexanemethanol was used, and 2-chloro-3-hydroxybenzaldehyde (1.38 g, 8.8 mmol) was used instead of 4-hydroxy-3-methylbenzaldehyde. Using the same method, except that triphenylphosphine was used in an amount of 2.54 g and 9.68 mmol, 1.89 g of an intermediate product, 2-chloro-3- (cyclohexylmethoxy) benzaldehyde, was obtained. The yield of the product was 85.5%.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (2-chloro-3- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione) (1.06 g, 76.3% yield)
  • Derivative 64 represented by the following formula was prepared in the following manner.
  • 3-cyclohexyl-1-propanol (1 g, 7.0 mmol) was used instead of cyclohexanemethanol in the process of preparing the derivative of Example 51, and 2-chloro-3-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde.
  • Roxybenzaldehyde (855 mg, 7.0 mmol) was used, and the intermediate product 2-chloro-3- (cyclohexylpropoxy) was obtained using the same method except that triphenylphosphine was used in an amount of 2.02 g, 7.7 mmol. 1.65 g of benzaldehyde was obtained, wherein the yield of the intermediate product was 83.8%.
  • Derivative 65 represented by the following formula was prepared in the following manner.
  • Derivative 66 represented by the following formula was prepared in the following manner.
  • silica gel column chromatography gave 0.86 g of 4-((4-acetylcyclohexyl) methic group) benzaldehyde (76.8% yield) using an eluting solvent in which hexane and ethyl acetate were mixed at 10: 1. Thereafter, the two compounds obtained above were used in the same manner as in Example 2, except that 4- (2-cyclomethoxy) -3-methylbenzaldehyde was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde.
  • Derivative 67 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3- (2-cyclohexylethoxy) 4-methoxybenzylidene) thiazolidione-2,4-dione (5- (3- (2-cyclohexylethoxy) -4-methoxybenzylidene) thiazolidine-2,4 -dione) (1.24 g, 87.2% yield)
  • Derivative 68 represented by the following formula was prepared in the following manner.
  • Derivative 69 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione (5- (3-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione) (1.19 g, 86.2% Yield)
  • a derivative 70 represented by the following formula was prepared in the following manner.
  • 3-phenyl-1-propanol (1 g, 7.3 mmol) was used instead of cyclohexanemethanol in the preparation of the derivative of Example 51, and 3-chloro-4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde.
  • Benzaldehyde (1.14 g, 7.3 mmol) was used, and the intermediate product 3-chloro-4- (3-phenylpropoxy was used in the same manner, except that triphenylphosphine was used in an amount of 2.11 g and 8.03 mmol. 1.48 g of benzaldehyde was obtained, with a yield of 73.6% of the intermediate product.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3-chloro-4- (3-phenylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro-4- (3-phenylpropoxy) benzylidene) thiazolidine-2,4 -dione) (1.13 g, 83.1% yield) was obtained.
  • Derivative 71 represented by the following formula was prepared in the following manner.
  • Derivative 72 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3- (benzyloxy) -2-chlorobenzylidene) thiazolidine-2,4-dione (5- (3- (benzyloxy) -2-chlorobenzylidene) thiazolidine-2,4-dione) (1.05 g , 75% yield).
  • Derivative 73 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (2-chloro-3-phenylethoxybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-3-phenylethoxybenzylidene) thiazolidine-2,4-dione) (1.07 g, 77.5% Yield).
  • Derivative 74 represented by the following formula was prepared in the following manner.
  • Example 51 In preparing the derivative of Example 51, 4-phenyl-1-butanol (1 g, 6.7 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde.
  • Benzaldehyde (1.05 g, 6.7 mmol) was used, and the intermediate product 2-chloro-3- (4-phenylbutoxy was used in the same manner, except that triphenylphosphine was used in an amount of 1.93 g and 7.37 mmol. 1.40 g of benzaldehyde was obtained, with a yield of 72.9% of the intermediate product.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (2-chloro-3- (4-phenylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (4-phenylbutoxy) benzylidene) thiazolidine-2,4 -dione) (1.10 g, 82.1% yield) was obtained.
  • Derivative 75 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (2-chloro-3- (3-phenylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (3-phenylpropoxy) benzylidene) thiazolidine-2,4 -dione) (1.12 g, 82.4% yield) was obtained.
  • Derivative 76 represented by the following formula was prepared in the following manner.
  • Derivative 77 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3-chloro-5-fluoro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro-5-fluoro-4- (2 -cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione) (1.0 g, 75.4% yield) was obtained.
  • Derivative 78 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3-chloro-4- (2-cyclohexylethoxy) -5-methoxybenzylidene) thiazolidine-2,4-dione (5- (3-chloro-4- (2-cyclohexylethoxy)- 5-methoxybenzylidene) thiazolidine-2,4-dione) (1.12 g, 84.2% yield) was obtained.
  • Derivative 79 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3- (2-cyclohexylethoxy) -4-nitrobenzylidene) thiazolidine-2,4-dione (5- (3- (2-cyclohexylethoxy) -4-nitrobenzylidene) thiazolidine-2, 4-dione) (1.24 g, 87% yield) was obtained.
  • Derivative 80 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (2-chloro-3- (2-cyclohexylethoxy) -4-methoxybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (2-cyclohexylethoxy)- 4-methoxybenzylidene) thiazolidine-2,4-dione) (1.04 g, 78.1% yield) was obtained.
  • Derivative 81 represented by the following formula was prepared in the following manner.
  • a 5- (4- (2-cyclohexylethoxy) represented by the above formula was carried out in the same manner, except that it was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the preparation process.
  • 2- (trifluoromethyl) benzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylethoxy) -2- (trifluromethyl) benzylidene) thiazolidine-2,4-dione) (1.06 g, 79.7% yield).
  • Derivative 82 represented by the following formula was prepared in the following manner.
  • Example 51 In preparing the derivative of Example 51, 4-cyclohexyl-1-butanol (1 g, 6.4 mmol) was used instead of cyclohexanemethanol, and 4-hydroxy-3- instead of 4-hydroxy-3-methylbenzaldehyde. Nitrobenzaldehyde (1.07 g, 6.4 mmol) was used, and the intermediate product 4- (2-cyclohexylbutoxy)-was used in the same manner except that triphenylphosphine was used in an amount of 1.85 g and 7.04 mmol. 1.32 g of 3-nitrobenzaldehyde were obtained, wherein the yield of the intermediate product was 81%.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (4- (2-cyclohexylbutoxy) -3-nitrobenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylbutoxy) -3-nitrobenzylidene) thiazolidine-2, 4-dione) (1.23 g, 77.8% yield) was obtained.
  • Derivative 83 represented by the following formula was prepared in the following manner.
  • Derivative 84 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5-4- (2-cyclohexylpropoxy) -3-methoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylpropoxy) -3-methoxybenzylidene) thiazolidine-2,4 -dione) (1.13 g, 83.1% yield) was obtained.
  • Derivative 85 represented by the following formula was prepared in the following manner.
  • Derivative 86 represented by the following formula was prepared in the following manner.
  • Example 85 The procedure of Example 85 was repeated except that 2-phenylethanol (1 g, 8.2 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution, and 2-chloro-4-phenyl as an intermediate product. 1.64 g (77% yield) of ethoxybenzaldehyde were obtained, and the obtained intermediate product was then used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative preparation of Example 51. The same procedure was followed except that 5- (2-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-4-phenylethoxybenzylidene) represented by the above formula.
  • Derivative 87 represented by the following formula was prepared in the following manner.
  • Example 85 The procedure of Example 85 was repeated except that 3-phenyl-1-propanol (1 g, 7.3 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution.
  • the intermediate product 2-chloro- 1.4 g (69.7% yield) of 4-phenylpropoxybenzaldehyde were obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethoxy) -3-methyl in the second step of the preparation of the derivative of Example 51.
  • a 5- (2-chloro-4-phenylpropoxybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-4) represented by the above formula was subjected to the same method except that it was used instead of benzaldehyde.
  • Derivative 88 represented by the following formula was prepared in the following manner.
  • Example 85 The procedure of Example 85 was repeated except that 4-phenyl-1-butanol (1 g, 6.7 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution.
  • the intermediate product 2-chloro- 1.39 g (72.4% yield) of 4-phenylbutoxybenzaldehyde were obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethoxy) -3-methyl in the second step of the preparation of the derivative of Example 51.
  • a 5- (2-chloro-4-phenylbutybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-4) represented by the above formula was subjected to the same method except that it was used instead of benzaldehyde.
  • Derivative 89 represented by the following formula was prepared in the following manner.
  • Example 51 In preparing the derivative of Example 51, 4- (2-hydroperoxypropyl-1-methylcyclohex-1-ene (1 g, 6.5 mmol) was used instead of cyclohexanemethanol, and 4-hydroxy-3 4-hydroxybenzaldehyde (0.79 g, 6.5 mmol) is used instead of methylbenzaldehyde, and the intermediate product 4- (2 is used in the same manner except that triphenylphosphine is used in an amount of 1.85 g and 7.05 mmol.
  • Derivative 90 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- [3-nitro-4- (2-thiomorpholine 1,1-dioxideethoxy) benzylidene] -2,4-thiazolidine dione (5- [3-nitro-4- (2-Thiomorpholine1 , 1-Dioxideethoxy) benzylidene] -2,4-thiazolidine dione) (0.88 g, 67.7% yield) was obtained.
  • Derivative 91 represented by the following formula was prepared in the following manner.
  • Example 51 In preparing the derivative of Example 51, 4-methyl-1-cyclohexanemethanol (1 g, 5.6 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3- instead of 4-hydroxy-3-methylbenzaldehyde. Hydroxybenzaldehyde (1.22 g, 7.8 mmol) was used, and the intermediate product 2-chloro-3-[(4- was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.49 g of methylcyclohexyl) methoxy] benzaldehyde was obtained, wherein the yield of the intermediate product was 74.1%.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- ⁇ 2-chloro-3-[(4-methylcyclohexyl) methoxy] benzylidene ⁇ -1,3-thiazolidine-2,4-dione (5- ⁇ 2-chloro-3-[(4 -methylcyclohexyl) methoxy] benzylidene ⁇ -1,3-thiazolidine-2,4-dione) (1.12 g, 81.2% yield) was obtained.
  • Derivative 92 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- ⁇ 2-chloro-3- [2- (propan-2-yloxy) ethoxy] benzylidene ⁇ -1,3-thiazolidine-2,4-dione 5- ⁇ 2-chloro-3- [2- (propan-2-yloxy) ethoxy] benzylidene ⁇ -1,3-thiazolidine-2,4-dione) (1.06 g, 75.7% yield) was obtained.
  • Derivative 93 represented by the following formula was prepared in the following manner.
  • Derivative 94 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- ⁇ 3-chloro-4- [2- (propan-2-yloxy) ethoxy] benzylidene ⁇ -1,3-thiazolidine-2,4-dione 5- ⁇ 3-chloro-4- [2- (propan-2-yloxy) ethoxy] benzylidene ⁇ -1,3-thiazolidine-2,4-dione) (1.09 g, 77.3% yield) was obtained.
  • Derivative 95 represented by the following formula was prepared in the following manner.
  • Example 85 The procedure of Example 85 was repeated except that the cyclohexanol (1 g, 10 mmol) solution was used instead of the benzyl alcohol (1 g, 9.2 mmol) solution. 1.74 g (86% yield) of siloxy) benzaldehyde was obtained, and the obtained intermediate product was then substituted for 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative preparation of Example 51.
  • Derivative 96 represented by the following formula was prepared in the following manner.
  • Example 85 The procedure of Example 85 was repeated except that the solution of cyclohexanemethanol (1 g, 9.2 mmol) was used instead of the solution of benzyl alcohol (1 g, 9.2 mmol).
  • the intermediate product 2-chloro-4- (3 1.67 g (85% yield) of -cyclohexylmethoxy) benzaldehyde was obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethoxy) -3- in the second step of the derivative preparation of Example 51.
  • a 5- (2-chloro-4- (3-cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5-) represented by the above formula was subjected to the same method except that it was used instead of methylbenzaldehyde.
  • (2-chloro-4- (3-cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione) (1.05 g, 75.5% yield) was obtained.
  • Derivative 97 represented by the following formula was prepared in the following manner.
  • Example 85 The procedure of Example 85 was repeated except that 3-cyclohexyl-1-propanol (1 g, 7.0 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution. 1.60 g (81.2% yield) of 4- (3-cyclohexylpropoxy) benzaldehyde was obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethy in the second step in the preparation of the derivative of Example 51.
  • Derivative 98 represented by the following formula was prepared in the following manner.
  • Example 85 The procedure of Example 85 was repeated except that 4-cyclohexyl-1-butanol (1 g, 6.4 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution. 1.56 g (83% yield) of -4- (3-cyclohexylbutoxy) benzaldehyde was obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethy in the second step of the derivative preparation of Example 51.
  • Derivative 99 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (2-chloro-3- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione) (1.12 g, 78.9% yield) was obtained.
  • Derivative 100 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (2-chloro-3- (cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione) (1.12 g, 83.6% yield) was obtained.
  • Derivative 101 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3-chloro-4- (2-thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro-4- (2- (thiophen- 2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) (1.21 g, 88.3% yield) were obtained.
  • Derivative 102 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (3-methoxy-4- (2- (thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-methoxy-4- (2- ( thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) (1.22 g, 88.4% yield) were obtained.
  • a derivative 103 represented by the following formula was prepared in the following manner.
  • the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51.
  • 5- (4-methoxy-3- (2-thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4-methoxy-3- (2- (thiophen) -2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) (1.26 g, 91.3% yield) were obtained.
  • Derivative 104 represented by the following formula was prepared in the following manner.

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Abstract

The present invention relates to a novel Thiazolidinedione derivative expressed by the following chemical formula (1) and uses thereof. More specifically, the present invention relates to a novel Thiazolidinedione derivative expressed by the following chemical formula (1) and a pharmaceutical composition comprising the same. The novel Thiazolidinedione derivative of the following chemical formula (1) according to the present invention can be effectively used for the prevention or treatment of cardiovascular disease, gastrointestinal disease and renal disease by inhibiting the activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) that decomposes prostaglandins, for preventing hair loss while stimulating hair growth, for osteogenic stimulation and for the treatment of burns.

Description

신규한 티아졸리딘디온 유도체 및 그의 용도Novel thiazolidinedione derivatives and uses thereof
본 발명은 신규한 티아졸리딘디온 유도체 및 이의 용도에 관한 것이다. 보다 구체적으로 본 발명은 신규한 티아졸리딘디온 유도체 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention relates to novel thiazolidinedione derivatives and their use. More specifically, the present invention relates to novel thiazolidinedione derivatives and pharmaceutical compositions comprising the same.
프로스타글란딘(prostaglandin)은 20개의 탄소로 이루어진 지방산 유도체로서 5개의 탄소로 이루어진 고리를 포함하고 있다. 이 물질은 1935년에 스웨덴의 생리학자 울프 폰 오일러가 발견했는데, 그는 이 물질이 전립선에서 분비된다고 생각하여 프로스타글란딘이라고 명명했다. 현재는 동물의 조직 내에 널리 존재하며, 다불포화 지방산으로부터 합성된 후 재빨리 대사된다고 알려져 있다. 이러한 프로스타글란딘은 그 형태에 따라 평활근 수축을 자극할 수 있으며, 일부 동물에서는 혈압을 낮추거나 높이고 혈액의 응집력을 감소시키거나 증가시키는 작용을 할 뿐만 아니라 막에 대한 이온 수송을 촉진시키고 염증을 자극하며 심장혈관 질환과 바이러스의 감염을 억제할 수 있는 작용도 하는 것으로 알려져 있다. Prostaglandin is a fatty acid derivative of 20 carbons and contains a ring of 5 carbons. The substance was discovered in 1935 by Swedish physiologist Wolf von Euler, who named it prostaglandin because he thought it was secreted from the prostate. It is presently widely present in the tissues of animals and is known to be quickly metabolized after synthesis from polyunsaturated fatty acids. These prostaglandins can stimulate smooth muscle contraction, depending on their form, and in some animals they act to lower or raise blood pressure, reduce or increase blood cohesion, as well as promote ion transport to the membrane, stimulate inflammation, and It is also known to act to inhibit vascular disease and viral infections.
한편 프로스타글란딘 및 이들의 동족체들은 화학적으로 불안정하고 생체 내에서 빠른 대사로 인해 짧은 유효기(effective life)를 갖는데, 이러한 이유는 프로스타글란딘 및 이들의 동족체가 일반적으로 하이드록실 및 카르복실기의 형태에서 활성부위를 가지는데 효소가 이러한 활성기를 빠르게 불활성화 시키기 때문이며, 또한 체내로부터 쉽게 제거되고 배출될 수 있을 만큼 작은 분자량으로 존재하기 때문이다(Narumiya S. 등, 1999, Physiol. Rev., 79(4), 1193-1226). 따라서 프로스타글란딘 및 이들 동족체들은 화학적으로 불안정하고 유효기가 매우 짧기 때문에 호흡기, 생식기, 신경, 내분비선 및 심장혈관계통 등의 질환 치료를 위한 사용에 심한 제한이 있었다.Prostaglandins and their analogs, on the other hand, are chemically unstable and have a short effective life due to rapid metabolism in vivo, which is why prostaglandins and their analogs generally have active sites in the form of hydroxyl and carboxyl groups. This is because enzymes rapidly inactivate these activators and are also present in molecular weights small enough to be easily removed and excreted from the body (Narumiya S. et al., 1999, Physiol. Rev. , 79 (4), 1193-). 1226). Therefore, since prostaglandins and their homologues are chemically unstable and have very short effective periods, prostaglandins and their homologues have severe restrictions on their use for the treatment of diseases such as the respiratory system, genitals, nerves, endocrine glands and cardiovascular system.
따라서 상기와 같은 문제점들을 해결하기 위하여 프로스타글란딘 및 이의 동족체들의 향상된 안정성, 광범위한 투여방법, 더 효과적인 활성 또는 더 긴 유효기를 제공하는 약제학적으로 수용할 수 있는 제제를 개발하기 위한 연구들이 진행되고 있는데, 이와 관련된 종래 기술들을 살펴보면, 대한민국 등록특허 제0598660호에는 우수한 활성을 위해 프로스타글란딘 수용체에 강하게 결합할 수 있는 5 - 티아 - ω - 치환 페닐 - 프로스타글란딘 Ｅ 유도체에 대한 내용이 개시되어 있고, 대한민국 등록특허 제0850133호에는 프로스타글란딘에 의한 부작용을 감소시키고 약리 효과를 최대화시킨 프로스타글란딘 나이트로옥시 유도체가 개시되어 있으며, 대한민국 공개특허 제2001-0023839호에는 ＦＰ 작동약으로 유용한 방향족 Ｃ16 - Ｃ20 - 치환된 테트라히드로 프로스타글란딘이 개시되어 있다. Therefore, in order to solve the above problems, studies are being conducted to develop pharmaceutically acceptable formulations that provide improved stability of prostaglandins and their homologues, a wider range of administration methods, more effective activities or longer effective periods. Looking at the related prior arts, Korean Patent No. 0598660 discloses the contents of 5 -thia-ω-substituted phenyl-prostaglandin E derivatives that can strongly bind to the prostaglandin receptor for excellent activity, and Korean Patent No. 0850133 No. discloses prostaglandin nitrooxy derivatives that reduce side effects caused by prostaglandins and maximize pharmacological effects, and Korean Patent Laid-Open No. 2001-0023839 discloses aromatic C16-C20-substituted tetrahydropropanes useful as Fp agonists. The other prostaglandin is disclosed.
한편, 프로스타글란딘은 생체 내에서 빠른 대사로 인해 짧은 생리활성을 갖게 되는데 이러한 대사과정의 첫 번째 단계는 산화과정으로서, 프로스타글란딘이 NAD+ 의존형 15-하이드록시프로스타글란딘 탈수소화효소(15-hydroxyprostaglandin dehydrogenase:15-PGDH)에 의해 불활성화된다(Ensor, C.M, & Tai, H.H., 1995, J. Lipid Mediator Cell Signalling 12:313-319).On the other hand, prostaglandins have short physiological activity due to rapid metabolism in vivo. The first step in this metabolic process is oxidation, where prostaglandins are NAD + dependent 15-hydroxyprostaglandin dehydrogenase (15-hydroxyprostaglandin dehydrogenase: 15-). PGDH) (Ensor, CM, & Tai, HH, 1995, J. Lipid Mediator Cell Signaling 12: 313-319).
15-하이드록시프로스타글란딘 탈수소화효소(15-PGDH)는 프로스타글란딘을 분해하는 효소로서 15-PGDH가 발현되지 않은 조직의 경우에는 프로스타글란딘의 양이 증가되어 있다. 또한, 15-PGDH 효소는 포유동물의 조직에 편재되어 있으며, 처음에는 태반, 폐 및 신장으로부터 추출되어 분리되었고(Krook M 등, 1990, Biochemistry, 29, 738~743), 이 효소의 기능은 C-15 위치의 하이드록시기(-OH)를 함유한 프로스타글란딘계 화합물을 산화시켜 15-케토프로스타글란딘(15-ketoprostaglandin)으로 전환시키고 따라서 상기 화합물의 생물학적인 활성을 잃게 만든다(Tai HH 등, 2002, Adv Exp Med Biol, 507, 245~250).15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is an enzyme that degrades prostaglandins, and the amount of prostaglandin is increased in tissues in which 15-PGDH is not expressed. In addition, 15-PGDH enzyme is ubiquitous in mammalian tissue, initially extracted and isolated from placenta, lung and kidney (Krook M et al., 1990, Biochemistry , 29, 738-743), and its function is C Prostaglandin-based compounds containing a hydroxyl group (-OH) at the -15 position are oxidized to convert to 15-ketoprostaglandin and thus lose the biological activity of the compound (Tai HH et al., 2002, Adv). Exp Med Biol , 507, 245-250).
한편, 최근 발표되는 연구 결과들에 의하면, 15-PGDH가 발암에 잠재적 역할을 하는 것으로 제시된 바 있는데, 즉, 인간 전립선암 세포에서 안드로젠을 처리시 처리하지 않은 세포에 비해 15-PGDH의 발현이 현저하게 증가되었고, 인간의 전립선암 세포가 주입된 누드 마우스 유래의 종양에서 15-PGDH의 발현이 증가된 것으로 나타났다(M.Tong., 2000, Biochem. Biophys. Res. Commun., 276, 77~81). 이에 많은 연구자들은 세포 내에서 15-PGDH의 발현을 억제시키거나 또는 감소시킨다면 암 발생을 억제할 수 있음을 예상하였다.Recent studies have shown that 15-PGDH plays a potential role in carcinogenesis, ie the expression of 15-PGDH is more pronounced in human prostate cancer cells than in cells treated with androgens. And increased expression of 15-PGDH in tumors from nude mice injected with human prostate cancer cells (M. Tong., 2000, Biochem. Biophys. Res. Commun ., 276, 77-81). ). Many researchers have anticipated that inhibiting or reducing the expression of 15-PGDH in cells can inhibit cancer development.
따라서 15-PGDH의 활성을 억제할 수 있는 억제제들에 관한 연구가 활발히 진행되고 있는데, 특히, 사이클로옥시게나제 억제제(cyclooxygenase inhibitor), 플라보노이드, 피토페놀계(phytophenolic) 화합물 및 퍼옥시좀 증식자-활성화 수용체 감마(peroxisome proliferator-activated receptor γ:PPAR γ)가 15-PGDH의 억제효과가 있다는 내용이 밝혀진 바 있다.  Therefore, there are active studies on inhibitors capable of inhibiting the activity of 15-PGDH, in particular cyclooxygenase inhibitors, flavonoids, phytophenolic compounds and peroxysome proliferators- It has been found that activating receptor gamma (peroxisome proliferator-activated receptor γ: PPAR γ) has an inhibitory effect of 15-PGDH.
이에 본 발명자들은 상기 화합물 이외에도 15-PGDH를 억제할 수 있는 새로운화합물을 연구하던 중, 신규한 티아졸리딘디온 유도체를 발견하였고 상기 유도체가 15-PGDH를 억제하는 활성이 우수할 뿐만 아니라 발모 촉진효과, 심혈관계 질환의 개선효과, 위장장애 개선 효과, 골형성효과, 화상치료효과 및 신장 장애를 개선할 수 있는 효과가 있음을 확인함으로써 본 발명을 완성하였다. Therefore, the present inventors found a new thiazolidinedione derivative while researching a new compound capable of inhibiting 15-PGDH in addition to the above compound, and the derivative not only has an excellent activity of inhibiting 15-PGDH, but also promotes hair growth. The present invention was completed by confirming that there is an effect of improving cardiovascular disease, gastrointestinal disorder, bone formation effect, burn treatment effect and kidney disorder.
따라서 본 발명의 목적은 신규한 티아졸리딘디온 유도체를 제공하는 것이다.It is therefore an object of the present invention to provide novel thiazolidinedione derivatives.
또한, 본 발명의 다른 목적은 상기 유도체를 유효성분으로 함유하는 탈모방지 및 발모촉진용 약학적 조성물을 제공하는 것이다. In addition, another object of the present invention to provide a pharmaceutical composition for preventing hair loss and promoting hair growth containing the derivative as an active ingredient.
또한, 본 발명의 다른 목적은 상기 유도체를 유효성분으로 함유하는 심혈관계 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. In addition, another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing the derivative as an active ingredient.
또한, 본 발명의 다른 목적은 상기 유도체를 유효성분으로 함유하는 위장질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. In addition, another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases containing the derivative as an active ingredient.
또한, 본 발명의 다른 목적은 상기 유도체를 유효성분으로 함유하는 신장질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. In addition, another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of kidney disease containing the derivative as an active ingredient.
또한, 본 발명의 다른 목적은 상기 유도체를 유효성분으로 함유하는 골형성용 조성물을 제공하는 것이다.  In addition, another object of the present invention to provide a composition for bone formation containing the derivative as an active ingredient.
또한, 본 발명의 다른 목적은 상기 유도체를 유효성분으로 함유하는 화상 치료용 조성물을 제공하는 것이다. In addition, another object of the present invention to provide a composition for treating burns containing the derivative as an active ingredient.
상기와 같은 본 발명의 목적을 달성하기 위해서, 본 발명은 신규한 티아졸리딘디온 유도체를 제공한다. In order to achieve the above object of the present invention, the present invention provides a novel thiazolidinedione derivative.
또한, 본 발명은 상기 유도체를 유효성분으로 함유하는 탈모방지 및 발모촉진용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for preventing hair loss and promoting hair growth, containing the derivative as an active ingredient.
또한, 본 발명은 상기 유도체를 유효성분으로 함유하는 심혈관계 질환의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing the derivative as an active ingredient.
또한, 본 발명은 상기 유도체를 유효성분으로 함유하는 위장질환의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases containing the derivative as an active ingredient.
또한, 본 발명은 상기 유도체를 유효성분으로 함유하는 신장질환의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention or treatment of kidney disease containing the derivative as an active ingredient.
또한, 본 발명은 상기 유도체를 유효성분으로 함유하는 골형성용 조성물을 제공한다. The present invention also provides a composition for bone formation containing the derivative as an active ingredient.
나아가 본 발명은 상기 유도체를 유효성분으로 함유하는 화상 치료용 조성물을 제공한다.Furthermore, the present invention provides a composition for treating burns containing the derivative as an active ingredient.
본 발명에 따른 신규한 티아졸리딘디온 유도체는 15-하이드록시프로스타글란딘 탈수소화효소를 저해하는 효과가 우수하므로 15-PGDH에 의해 유발될 수 있는 심혈관계 질환, 위장질환 및 신장질환을 예방 및 치료할 수 있는 효과가 있고, 탈모를 방지하고 발모를 촉진시키는 효과가 있으며, 골형성을 촉진시키는 효과 뿐만 아니라 화상을 치료할 수 있는 효과가 있다.Since the novel thiazolidinedione derivatives according to the present invention have an excellent effect of inhibiting 15-hydroxyprostaglandin dehydrogenase, it is possible to prevent and treat cardiovascular diseases, gastrointestinal diseases and kidney diseases which may be induced by 15-PGDH. It is effective in preventing hair loss and promoting hair growth, and in promoting bone formation as well as treating the burn.
본 발명은 하기 화학식 1로 표시되는 신규한 티아졸리딘디온 유도체를 제공함을 특징으로 한다.The present invention is characterized by providing a novel thiazolidinedione derivative represented by the following formula (1).
<화학식 1><Formula 1>
Figure PCTKR2009007995-appb-I000001
Figure PCTKR2009007995-appb-I000001
상기 식에서, A 및 A' 는 각각 독립적으로 O 또는 S 이고, R1은 수소 또는 CH2CH2OH 이며, R2, R3, R4 및 R5는 각각 독립적으로 수소, 니트로기, 아민, 알콕시, 알킬, 트리플루오로메틸, 카르복실, 할로겐 또는
Figure PCTKR2009007995-appb-I000002
일 수 있고,Wherein A and A 'are each independently O or S, R 1 is hydrogen or CH 2 CH 2 OH, and R 2 , R 3 , R 4 and R 5 are each independently hydrogen, nitro group, amine, Alkoxy, alkyl, trifluoromethyl, carboxyl, halogen or
Figure PCTKR2009007995-appb-I000002
Can be,
이때 상기
Figure PCTKR2009007995-appb-I000003
는 벤젠고리의 3번 또는 4번 탄소 위치에서 결합할 수 있으며, R6는 수소, 메틸, 에틸, 치환 또는 비치환 (헤테로)사이클로알킬, (헤테로)사이클로알케닐 또는 (헤테로)아릴로 이루어진 군 중에서 선택될 수 있고, 점선은 단일 또는 이중결합을 나타낸 것이고, n은 0 내지 5의 정수일 수 있다.At this time
Figure PCTKR2009007995-appb-I000003
May be bonded at the 3 or 4 carbon position of the benzene ring, and R 6 is hydrogen, methyl, ethyl, substituted or unsubstituted (hetero) cycloalkyl, (hetero) cycloalkenyl or (hetero) aryl group; It may be selected from, dotted line represents a single or double bond, n may be an integer of 0 to 5.
또한, 상기 화학식에서 R3가
Figure PCTKR2009007995-appb-I000004
일 경우에는 R2, R4 및 R5가 각각 독립적으로 H, NO2, NH2, CH3, Cl, Br, F, COOH, CF3, CH3O, CH3CH2O로 이루어진 군 중에서 선택될 수 있고, 상기 R4가
Figure PCTKR2009007995-appb-I000005
일 경우에는 R2, R3 및 R5가 각각 독립적으로 H, NO2, NH2, CH3, Cl, Br, F, COOH, CF3, CH3O, CH3CH2O로 이루어진 군 중에서 선택될 수 있다. In addition, in the above formula, R 3
Figure PCTKR2009007995-appb-I000004
In the case of R 2 , R 4 and R 5 are each independently H, NO 2 , NH 2 , CH 3 , Cl, Br, F, COOH, CF 3 , CH 3 O, CH 3 CH 2 O Can be selected, wherein R 4 is
Figure PCTKR2009007995-appb-I000005
In the case of R 2 , R 3 and R 5 are each independently H, NO 2 , NH 2 , CH 3 , Cl, Br, F, COOH, CF 3 , CH 3 O, CH 3 CH 2 O Can be selected.
한편, 본 발명에 따른 상기 화학식 1로 표시되는 유도체를 기술하기 위해 사용된 여러 가지 용어에 대한 정의를 설명하면 다음과 같으며, 하기 기술한 용어들에 대한 정의들은 개별적이거나 또는 큰 그룹의 일부분으로서 특정 경우에 한하여 다르게 한정하지 않는 한, 본원의 전체에 걸쳐 사용된 용어에 적용된다. Meanwhile, the definitions of various terms used to describe the derivative represented by Formula 1 according to the present invention are as follows. Definitions for the terms described below are individual or as part of a large group. Unless defined otherwise, in certain instances, the terminology used throughout this application is applicable.
상기에서 알킬이란 용어는 1 내지 20개의 탄소 원자, 바람직하게는 1 내지 7개의 탄소 원자를 갖는 비치환 또는 치환된 직쇄 또는 분지쇄 탄화수소기를 나타낸다. 대표적인 비치환된 알킬기는 메틸, 에틸, 프로필, 이소프로필, n-부틸, t-부틸, 이소부틸, 펜틸, 헥실, 이소헥실, 헵틸, 4,4-디메틸펜틸, 옥틸 등을 포함한다. 치환된 알킬기는 할로, 히드록시, 시클로알킬, 알카노일, 알콕시, 알킬옥시알콕시, 알카노일옥시, 아미노, 알킬아미노, 디알킬아미노, 아실아미노, 카르바모일, 티올, 알킬티오, 알킬티오노, 술포닐, 술폰아미도, 술파모일, 니트로, 시아노, 카르복시, 알콕시카르보닐, 아릴, 알케닐, 알키닐, 아랄콕시, 구아니디노, 인돌릴, 이미다졸릴, 푸릴, 티에닐, 티아졸릴, 피롤리딜, 피리딜, 피리미딜, 피페리딜 및 모르폴리닐로 이루어진 군중에서 선택된 하나 이상에 의해 치환된 알킬기를 포함하지만, 이에 한정되지는 않는다. The term alkyl herein denotes an unsubstituted or substituted straight or branched chain hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. Representative unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups are halo, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, Sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkyloxy, guanidino, indolyl, imidazolyl, furyl, thienyl, thia Alkyl groups substituted by one or more selected from the group consisting of zolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl and morpholinyl, but are not limited to these.
할로겐이란 용어는 불소, 염소, 브롬 및 요오드를 나타낸다. The term halogen refers to fluorine, chlorine, bromine and iodine.
알케닐이란 용어는, 2개 이상의 탄소 원자를 갖고 이중 결합을 포함하는 임의의 상기 알킬기를 나타내며, 2 내지 4개의 탄소 원자를 갖는 것이 바람직하다. The term alkenyl refers to any of the above alkyl groups having two or more carbon atoms and comprising a double bond, preferably having two to four carbon atoms.
아릴이란 용어는 고리 부분에 6 내지 12개의 탄소 원자를 갖는 모노사이클릭 또는 비사이클릭 방향족 탄화수소기, 예를 들어 페닐, 나프틸, 테트라히드로나프틸, 비페닐 및 디페닐기를 나타내고, 이들 각각은 1 내지 4개의 치환기, 예를 들어 알킬, 할로, 히드록시, 알콕시, 아실, 알카노일옥시, 임의로 치환된 아미노, 티올, 알킬티오, 니트로, 시아노, 카르복시, 카르복시알킬, 알콕시카르보닐, 카르바모일, 알킬티오노, 술포닐, 술폰아미도, 헤테로시클릴 등으로 임의로 치환될 수 있다. The term aryl denotes monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, for example phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each of which 1 to 4 substituents such as alkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, optionally substituted amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, carba Optionally substituted with moyl, alkylthioo, sulfonyl, sulfonamido, heterocyclyl and the like.
"사이클로알킬"이란 용어는, 3 내지 12개의 탄소 원자를 갖는 임의로 치환된 모노사이클릭, 비사이클릭 또는 트리사이클릭 탄화수소기를 나타내고, 이들 각각은 하나 이상의 치환기, 예를 들어 알킬, 할로, 옥소, 히드록시, 알콕시, 알카노일, 아실아미노, 카르바모일, 알킬아미노, 디알킬아미노, 티올, 알킬티오, 니트로, 시아노, 카르복시, 카르복시알킬, 알콕시카르보닐, 술포닐, 술폰아미도, 술파모일, 헤테로시클릴 등으로 치환될 수 있다. The term “cycloalkyl” denotes an optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon group having 3 to 12 carbon atoms, each of which is one or more substituents such as alkyl, halo, oxo, Hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl , Heterocyclyl, and the like.
헤테로사이클로"란 용어는 임의로 치환된 완전 포화 또는 불포화, 방향족 또는 비방향족 사이클릭기를 나타내는 고리계로서, 하나 이상의 탄소 원자를 포함하는 고리에 하나 이상의 헤테로 원자를 갖는다. 헤테로원자를 포함하는 헤테로사이클릭기의 각 고리는 질소 원자, 산소 원자 및 황 원자로부터 선택되는 1, 2 또는 3개의 헤테로원자를 가질 수 있고, 헤테로사이클릭기는 헤테로원자 또는 탄소 원자에 결합될 수 있다.  Heterocyclo "is a ring system that represents an optionally substituted fully saturated or unsaturated, aromatic or non-aromatic cyclic group, having at least one hetero atom in a ring containing at least one carbon atom. Heterocyclic comprising heteroatoms Each ring of the group may have one, two or three heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and the heterocyclic groups may be bonded to heteroatoms or carbon atoms.
바람직하게 상기 화학식 1로 표시되는 신규한 티아졸리딘디온(thiazolidinedione) 유도체의 구체예로는 본원의 실시예 1 내지 130에서 제조된 유도체들일 수 있다.  Preferably, specific examples of the thiazolidinedione derivative represented by Chemical Formula 1 may be derivatives prepared in Examples 1 to 130 of the present application.
또한, 본 발명은 상기 화학식 1로 표시되는 티아졸리딘디온 유도체의 염, 바람직하게는 약학적으로 허용되는 염을 제공한다. 상기 약학적으로 허용되는 염은 순수한 의학적 판단의 범위 내에서 과다한 독성, 자극 및 부작용 등의 유발 없이 사람 및 하등 동물의 조직과 접촉하여 사용하기에 적합한 염을 의미한다. 상기 약학적으로 허용되는 염은 당 분야에 잘 알려져 있다(S.M. Berge et al., 1977, J. Parmaceutical Sciences, 66:1). 상기 염은 본 발명의 유도체 화합물을 최종적으로 분리, 정제 및 합성하는 동안에 동일반응계에서 제조하거나 별도로 무기 염기 또는 유기 염기와 반응시켜 제조할 수 있다. 상기 약학적으로 허용되는 염으로는 본 발명의 유도체 화합물이 산성기를 함유하고 있을 경우, 염기와 염을 형성할 수 있으며, 이러한 염으로는 예를 들면, 이에 한정되지는 않으나 리튬염, 나트륨염 또는 칼륨염과 같은 알칼리금속과의 염; 바륨 또는 칼슘과 같은 알칼리토금속과의 염; 마그네슘염과 같은 기타 금속과의 염; 디시클로헥실아민과의 염과 같은 유기 염기염; 리신 또는 아르기닌과 같은 염기성 아미노산과의 염을 포함할 수 있다. 또한, 본 발명의 유도체 화합물이 분자 내에 염기성 기를 함유하는 경우에는 산부가염을 형성할 수 있으며, 이러한 산부가염의 예로는, 이에 한정되지는 않으나, 무기산, 특히 할로겐화수소산(예컨대, 불소화수소산, 브롬화수소산, 요오드화수소산 또는 염소화수소산), 질산, 탄산, 황산 또는 인산과의 염; 메탄술폰산, 트리플루오로메탄술폰산 또는 에탄술폰산과 같은 저급알킬 술폰산과의 염; 벤젠술폰산 또는 p-톨루엔술폰산과의 염; 아세트산, 푸마르산, 타르타르산, 옥살산, 말레산, 말산, 숙신산 또는 시트르산과 같은 유기카르복실산과의 염; 및 글루탐산 또는 아스파르트산과 같은 아미노산과의 염을 포함할 수 있다.In addition, the present invention provides a salt of a thiazolidinedione derivative represented by Chemical Formula 1, preferably a pharmaceutically acceptable salt. The pharmaceutically acceptable salts refer to salts suitable for use in contact with tissues of humans and lower animals without causing excessive toxicity, irritation and side effects within the scope of pure medical judgment. Such pharmaceutically acceptable salts are well known in the art (SM Berge et al ., 1977, J. Parmaceutical Sciences , 66: 1). The salts can be prepared in situ during the final separation, purification and synthesis of the derivative compounds of the invention or separately by reaction with an inorganic base or an organic base. As the pharmaceutically acceptable salt, when the derivative compound of the present invention contains an acidic group, it may form a salt with a base. Examples of the salt include, but are not limited to, lithium salt, sodium salt or Salts with alkali metals such as potassium salts; Salts with alkaline earth metals such as barium or calcium; Salts with other metals such as magnesium salts; Organic base salts such as salts with dicyclohexylamine; Salts with basic amino acids such as lysine or arginine. In addition, when the derivative compound of the present invention contains a basic group in a molecule, acid addition salts may be formed. Examples of such acid addition salts include, but are not limited to, inorganic acids, particularly hydrofluoric acid (for example, hydrofluoric acid and hydrobromic acid). , Hydroiodic acid or hydrochloric acid), salts with nitric acid, carbonate, sulfuric acid or phosphoric acid; Salts with lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; Salts with benzenesulfonic acid or p-toluenesulfonic acid; Salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; And salts with amino acids such as glutamic acid or aspartic acid.
또한, 본 발명은 화학식 1로 표시되는 신규한 티아졸리딘디온 유도체의 수화물 또는 용매화물의 형태로 된 유도체를 포함할 수 있다(J. M. Keith, 2004, Trahedron Letters, 45(13), 2739-2742). The present invention may also include derivatives in the form of hydrates or solvates of the novel thiazolidinedione derivatives represented by Formula 1 (JM Keith, 2004, Trahedron Letters , 45 (13), 2739-2742). .
본 발명에 따른 상기 화학식 1의 신규한 티아졸리딘디온(thiazolidinedione) 유도체는 천연으로부터 분리되거나 당 업계에 공지된 티아졸리딘디온계 화합물의 화학적 합성법으로 제조될 수 있으며, 통상적으로 티아졸리딘디온의 5 부분에 치환될 치환기 화합물들을 적절한 반응용매와 함께 반응시켜 중간체 생성물을 수득한 후, 상기 중간체 생성물을 다시 2,4-티아졸리딘디온과 함께 적절한 반응용매에서 반응시킴으로써 본 발명에 따른 유도체 화합물을 제조할 수 있다.  The novel thiazolidinedione derivatives of Formula 1 according to the present invention may be isolated from nature or prepared by chemical synthesis of thiazolidinedione-based compounds known in the art. The derivative compound according to the present invention is reacted by reacting the substituent compound to be substituted at 5 parts with an appropriate reaction solvent to obtain an intermediate product, and then reacting the intermediate product with 2,4-thiazolidinedione in an appropriate reaction solvent. It can manufacture.
상기 제조과정에서 사용될 수 있는 반응용매로는 반응에 관여하지 않는 한 특별한 제한은 없으며, 예를 들면 디에틸 에테르, 테트라히드로푸란, 디옥산 등의 에테르류; 디클로로메탄, 클로로포름 등의 할로겐화 탄화수소류; 피리딘, 피페리딘, 트리에틸아민 등의 아민류, 아세톤; 메틸에틸케톤, 메틸이소부틸 등의 알킬케톤류; 메탄올, 에탄올, 프로판올 등의 알코올류; N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 아세토니트릴, 디메틸술폭시드, 헥사메틸인산트리아미드 등의 비프로톤성 극성용매를 들 수 있으며, 특히 통상적으로 유기합성에서 사용되는 비반응성 유기용매 중에서 딘-스탁 트랩에 의해 반응 중 생성되는 물을 분리할 수 있는 용매가 선호된다. 이러한 용매의 예로는, 벤젠, 톨루엔, 크실렌 등이 있으나 이에 한정되지는 않는다. 반응 생성물의 분리 및 정제는 유기합성에서 통상적으로 수행되는 농축, 추출 등의 과정을 통해 이루어지며, 필요에 따라 실리카겔 상에서 컬럼 크로마토그래피에 의한 정제 작업을 통해 분리 및 정제를 수행할 수 있다. The reaction solvent that can be used in the production process is not particularly limited as long as it is not involved in the reaction, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane; Halogenated hydrocarbons such as dichloromethane and chloroform; Amines such as pyridine, piperidine and triethylamine, acetone; Alkyl ketones such as methyl ethyl ketone and methyl isobutyl; Alcohols such as methanol, ethanol and propanol; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, hexamethyl phosphate triamide, and the like, and especially non-reactive used in organic synthesis. Among the organic solvents, a solvent capable of separating the water generated during the reaction by the Dean-Stark trap is preferred. Examples of such a solvent include, but are not limited to, benzene, toluene, xylene, and the like. Separation and purification of the reaction product is carried out through a process such as concentration, extraction, and the like, which is commonly performed in organic synthesis, and separation and purification may be performed through purification by column chromatography on silica gel, if necessary.
본 발명은 또한 신규한 티아졸리딘디온(thiazolidinedione) 유도체의 제조방법들에 대한 임의의 변형을 포함하고, 여기서 그의 임의의 단계에서 수득할 수 있는 중간체 생성물은 나머지 단계들의 출발물질로 사용될 수 있으며, 상기 출발물질은 반응 조건하에 반응계 내에서 형성되거나, 반응 성분들은 그의 염 또는 광학적으로 거울상체의 형태로 사용될 수 있다. The invention also includes any modification to the methods for the preparation of novel thiazolidinedione derivatives, wherein the intermediate product obtainable at any stage thereof can be used as starting material for the remaining stages, The starting material can be formed in the reaction system under reaction conditions, or the reaction components can be used in the form of its salts or optically enantiomers.
또한 본 발명에 따른 신규한 티아졸리딘유도체는 상기 유도체를 제조하기 위해 사용된 치환기들의 종류, 중간체 생성물 및 제조방법의 선택에 따라 가능한 이성질체, 예컨대 실질적으로 순수한 기하학적(시스 또는 트랜스) 이성질체, 광학 이성질체(거울상체) 또는 라세미체의 형태일 수 있으며, 이러한 가능한 이성질체 모두 본 발명의 영역에 포함된다.  The novel thiazolidine derivatives according to the invention are also possible isomers, such as substantially pure geometric (cis or trans) isomers, optical isomers, depending on the type of substituents used to prepare the derivatives, the intermediate product and the method of preparation. (Enantiomers) or racemates, all such possible isomers are included within the scope of the present invention.
한편, 본 발명에 따른 상기 화학식 1로 표시되는 신규한 티아졸리딘디온(thiazolidinedione) 유도체는 15-하이드록시 프로스타글란딘 탈수소화효소(15-PGDH)를 억제 또는 저해하는 활성을 가지고 있는 특징이 있다. On the other hand, the novel thiazolidinedione derivative represented by the formula (1) according to the present invention is characterized by having an activity of inhibiting or inhibiting 15-hydroxy prostaglandin dehydrogenase (15-PGDH).
본 발명의 일실험예에서는, 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체들이 15-하이드록시 프로스타글란딘 탈수소화효소(15-PGDH)를 억제 또는 저해하는 활성이 있는지를 확인하기 위하여, 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체를 세포에 처리한 후, 발생되는 NADH의 양을 측정하였는데, 이는 15-PGDH가 활성이 높을 경우 NAD+가 환원되어 NADH를 생성하면서 프로스타글란딘을 산화시켜 불활성인 15-케토프로스타글란딘을 생성하기 때문에 NADH의 양을 측정함으로써 15-PGDH의 활성도를 확인할 수 있기 때문이다. 따라서 상기와 같은 실험을 수행한 결과, 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체가 15-PGDH를 억제하는 활성이 있는 것을 확인할 수 있었다(실험예 1 참조).In one experimental example of the present invention, in order to determine whether the novel thiazolidinedione derivatives according to the present invention have activity to inhibit or inhibit 15-hydroxy prostaglandin dehydrogenase (15-PGDH), After treatment with a new thiazolidinedione derivative according to the invention, the amount of NADH generated was measured. When 15-PGDH had high activity, NAD + was reduced to oxidize prostaglandin while generating NADH. This is because the activity of 15-PGDH can be confirmed by measuring the amount of NADH since it produces inactive 15-ketoprostaglandin. Therefore, as a result of the above experiment, it was confirmed that the novel thiazolidinedione derivative according to the present invention has an activity of inhibiting 15-PGDH (see Experimental Example 1).
따라서 본 발명자들은 본 발명의 신규한 티아졸리딘디온(thiazolidinedione) 유도체가 15-PGDH의 저해자라는 것을 확인할 수 있었고, 본 발명의 유도체를 15-PGDH에 의해 유발될 수 있는 질환들의 예방 또는 치료에 사용될 수 있음을 예상할 수 있었다.  Therefore, the present inventors have confirmed that the novel thiazolidinedione derivative of the present invention is an inhibitor of 15-PGDH, and the derivative of the present invention can be used for the prevention or treatment of diseases which may be caused by 15-PGDH. Could be expected.
한편, 프로스타글란딘은 모발의 성장에 중요한 역할을 한다고 알려진 바 있으며, 특히 모발의 밀도를 유지 또는 증가시키기 위해서는 모낭 또는 그 인근 피부 환경의 다양한 구역에서 다양한 타입(A2, F2a, E2)의 프로스타글란딘의 내부 저장이 매우 필수적인 것으로 밝혀진 바 있다(Colombe L 등, 2007, Exp. Dermatol, 16(9), 762-9). 그러나 프로스타글란딘의 분해에 특정적으로 관여하는 효소가 머리카락의 생존을 위한 결정적인 구역인 머리카락의 진피 유두에 존재하고 있으며, 15-PGDH가 프로스타글란딘, 특히, PGF2a 및 PGE2를 비활성화시켜 두피를 손상시키고 탈모를 유발시키는 것으로 알려진 바 있다(Michelet JF 등, 2008, Exp. Dermatol, 17(10), 821-8). On the other hand, prostaglandins have been known to play an important role in hair growth, and in order to maintain or increase hair density, prostaglandins of various types (A 2 , F 2a , E 2 ) in various zones of the hair follicle or nearby skin environment are known. Has been found to be very essential (Colombe L et al., 2007, Exp. Dermatol, 16 (9), 762-9). However, enzymes that are specifically involved in the breakdown of prostaglandins are present in the dermal papilla of the hair, a critical area for hair survival, and 15-PGDH inactivates prostaglandins, especially PGF 2a and PGE 2 , damaging the scalp and causing hair loss. (Michelet JF et al., 2008, Exp. Dermatol , 17 (10), 821-8).
따라서 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체 는 프로스타글란딘을 분해하는 15-하이드록시 프로스타글란딘 탈수소화효소(15-PGDH)를 억제 또는 저해하는 활성을 가지고 있으므로 두피의 손상을 개선할 수 있고 탈모를 방지할 수 있으며 발모를 촉진시킬 수 있는 효과가 있다. Therefore, the novel thiazolidinedione derivatives according to the present invention have an activity of inhibiting or inhibiting 15-hydroxy prostaglandin dehydrogenase (15-PGDH) that degrades prostaglandins, thereby improving scalp damage. It can prevent hair loss and has the effect of promoting hair growth.
그러므로 본 발명은 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체를 유효성분으로 함유하는 탈모방지 및 발모촉진용 약학적 조성물을 제공한다.  Therefore, the present invention provides a pharmaceutical composition for preventing hair loss and promoting hair growth, which contains the novel thiazolidinedione derivative according to the present invention as an active ingredient.
상기에서 탈모(alopecia)"란 부분적 또는 일반적 영구 모발의 손실을 갖는 모낭 상태 전체를 말하며, 상기 탈모 및 발모의 대상으로는 인간의 케라틴 섬유, 특히 모발, 눈썹, 속눈썹, 턱수염 및 콧수염 등 일 수 있다. The term "alopecia" refers to the entire hair follicle state with partial or general permanent hair loss, and the target of hair loss and hair growth may be human keratin fibers, in particular hair, eyebrows, eyelashes, beards, and mustaches. .
또한, 본 발명은 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체를 유효성분으로 함유하는 심혈관계 질환의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing a novel thiazolidinedione derivative according to the present invention as an active ingredient.
체내에서 생성된 프로스타글란딘 동족체를 포함하는 프로스타글란딘은 혈관벽의 적절한 작용을 유지하는 역할을 하는 것으로 알려져 있는데, 특히 혈액 흐름이 가능하도록 혈관을 이완시키고, 혈소판 응집을 방지하며, 혈관벽을 둘러싸는 평활근 세포 증식의 조절에 기여하는 것으로 알려져 있다(Yan. Cheng 등, 2006, J. Clin., Invest). 또한 프로스타글란딘의 생성이 억제되거나 또는 그 활성을 잃게 될 경우, 혈관벽 내막의 퇴화, 혈소판의 응집 및 평활근의 세포작용의 혼란 등이 유발되어 심혈관계 질환을 초래하게 되며, 특히 고혈압의 경우에는 혈관에서의 프로스타글란딘 생성이 감소되는 것으로 밝혀진 바 있다(Tang EH, 2008, Cardiovasc Res.,78(1),130-8).Prostaglandins, including the prostaglandin homologues produced in the body, are known to play a role in maintaining the proper functioning of the blood vessel wall, especially in the smooth muscle cell proliferation that relaxes blood vessels to prevent blood flow, prevents platelet aggregation, and surrounds the blood vessel wall. It is known to contribute to regulation (Yan. Cheng et al., 2006, J. Clin., Invest ). In addition, when the production of prostaglandins is inhibited or the activity is lost, degeneration of the lining of the blood vessel wall, aggregation of platelets and disruption of smooth muscle cells may be caused, leading to cardiovascular diseases, particularly in the case of high blood pressure. Prostaglandin production has been shown to be reduced (Tang EH, 2008, Cardiovasc Res ., 78 (1), 130-8).
따라서 본 발명에 따른 신규한 유도체 화합물들은 프로스타글란딘을 분해하는 15-PGDH를 억제 또는 저해하는 활성을 가지고 있으므로 세포내에서 프로스타글란딘(PGE2)을 저장하고 활성화시켜 심혈관계 질환을 예방하거나 또는 치료할 수 있다.Therefore, since the novel derivative compounds according to the present invention have the activity of inhibiting or inhibiting 15-PGDH that degrades prostaglandins, prostaglandins (PGE 2 ) can be stored and activated in cells to prevent or treat cardiovascular diseases.
상기 심혈관계 질환이란 혈관벽의 내막이 퇴화되거나 혈소판의 응집 또는 평활근의 세포작용 조절에 이상이 생겨 발생되거나, 혈액 내에 저밀도 지단백질 콜레스테롤(Low Density Lipoprotein cholesterol; 이하 'LDL-콜레스테롤'이라 함), 콜레스테롤 및 중성지방이 비정상적으로 높아 고콜레스테롤 혈증(hypercholesterolemia)에 의해 발생되는 질환을 모두 포함하는 것으로서 이러한 심혈관계 질환의 예로는, 이에 제한되지는 않으나, 동맥경화, 고혈압, 협심증, 고지혈증, 심근경색 및 심부전 등이 포함된다.  The cardiovascular disease is caused by degeneration of the lining of the blood vessel wall or abnormality in the regulation of platelet aggregation or smooth muscle cell function, low density lipoprotein cholesterol (hereinafter referred to as 'LDL-cholesterol'), cholesterol and Examples of such cardiovascular diseases include, but are not limited to, arteriosclerosis, hypertension, angina pectoris, hyperlipidemia, myocardial infarction and heart failure, including all diseases caused by hypercholesterolemia due to abnormally high triglycerides This includes.
또한, 본 발명은 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체를 유효성분으로 함유하는 위장질환의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases, which contains the novel thiazolidinedione derivative according to the present invention as an active ingredient.
위장질환의 대표적인 질환인 위염과 위궤양은 위장관 점막이 위산에 의해 소화되어 궤양을 형성하는 상태를 말하는 것으로서, 위벽은 일반적으로 점막층, 점막하층, 근육층 및 장막으로 구성되어 있는데, 위염은 점막이 손상된 상태이고, 위궤양은 점막하층 또는 근육층까지 손상된 경우를 말한다. 그러나 위염 및 위궤양은 발생빈도가 높은 것에 비해 발생 원인이 정확히 밝혀져 있지 않으며, 단지 공격인자와 방어인자의 불균형, 즉 공격인자의 증가나 방어인자의 약화에 의해 발생하는 것으로 알려져 있다. 공격인자의 증가 요인으로는 산, 펩신분비의 증가 등을 들 수가 있고 방어 인자의 약화 요인으로는 위점막의 구조나 형태의 결손 및 점액분비의 감소와 중탄산 이온 분비의 감소 및 프로스타글란딘 생산의 저하 등을 들 수 있다. 한편, 현재 사용되고 있는 위염 및 위궤양의 치료제로는 위산의 분비량에는 영향을 주지 않고 이미 생성된 위산을 중화시키는 제산제, 위산의 분비를 억제하는 약제, 프로스타글란딘의 분비 촉진제 및 위벽 코팅제 등 방어인자를 증강시키는 약제들이 사용되고 있으며, 특히 위점막의 보호 및 방어 작용을 유지하는데 있어서 프로스타글란딘의 역할은 매우 필수적인 것으로 알려져 있다(Wallace JL., 2008, Physiol Rev., 88(4), 1547-65, S. J. Konturek 등, 2005, Journal of Physiology and Pharmacology, 56(5), 5~31) Gastritis and gastric ulcers, which are representative diseases of the gastrointestinal diseases, refer to a condition in which the gastrointestinal mucosa is digested by gastric acid to form ulcers. And gastric ulcer refers to a case of damage to the submucosal or muscular layer. However, gastritis and gastric ulcers are not known to have a high degree of incidence, but are known to be caused only by an imbalance between attackers and defenders, that is, increase in attackers or weakening of defenders. Factors that increase the attack factor include increased acid and pepsin secretion, and factors that weaken the protective factor include deficiency in the structure and form of the gastric mucosa, decreased mucus secretion, decreased bicarbonate ion secretion, and decreased prostaglandin production. Can be mentioned. On the other hand, currently used treatment agents for gastritis and gastric ulcers do not affect the amount of gastric acid secretion, but neutralize the already produced gastric acid, drugs that inhibit the secretion of gastric acid, prostaglandin secretion accelerators and gastric wall coatings to enhance defense factors such as Drugs are being used, and the role of prostaglandins is particularly essential in maintaining the protective and protective action of the gastric mucosa (Wallace JL., 2008, Physiol Rev. , 88 (4), 1547-65, SJ Konturek et al., 2005, Journal of Physiology and Pharmacology , 56 (5), 5--31)
따라서 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체는 위점막을 보호하는 프로스타글란딘을 분해하는 15-PGDH를 억제 또는 저해하는 활성이 있으므로 위장질환, 특히 위염 및 위궤양을 예방 또는 치료할 수 있는 효과가 있다. Therefore, the novel thiazolidinedione derivatives according to the present invention have an activity of inhibiting or inhibiting 15-PGDH that degrades prostaglandins that protect the gastric mucosa, thereby preventing or treating gastrointestinal diseases, especially gastritis and gastric ulcers. There is.
또한, 신장에서 프로스타글란딘은 신장의 혈류를 조절하고 신혈관 및 관 효과 모두에 의해 뇨형성을 조절하는 것으로 알려져 있다. 이와 관련된 임상 연구에 따르면, 프로스타글란딘 1 (PGE1)은 만성 신장 질환 환자들의 크레아티닌 정제 개선, 신장 이식 환자의 이식 거부 및 사이클로스포린 독성 방지, 당뇨 신증 환자의 뇨 중 알부민 배출 속도 및 N-아세틸-β-D-글루코사미니다제 수치를 감소시키는 효과가 있는 것으로 밝혀진 바 있으며, PGE1, PGE2 및 PGI2와 같은 프로스타글란딘 화합물들을 정맥내 투여함으로써 신장기능 장애를 예방하는 방법이 개시된 바 있다(Porter, Am., 1989, J. Cardiol., 64: 22E-26E, 미국등록특허 제 5,807,895 호 참조). 또한, 프로스타글란딘은 신장에서 혈관을 확장하는 혈관 확장제의 역할을 하며, 신장에서 프로스타글란딘의 생성이 억제될 경우 신장 장애를 초래하는 것으로 알려져 있다(Hao. CM, 2008, Annu Rev Physiol, 70, 357~77).In addition, prostaglandins in the kidney are known to regulate blood flow in the kidney and to regulate urinary formation by both renal and vascular effects. Clinical studies have shown that prostaglandin 1 (PGE 1 ) improves creatinine purification in patients with chronic kidney disease, prevents transplant rejection and cyclosporin toxicity in patients with kidney transplantation, rate of albumin excretion in urine in diabetic nephropathy, and N -acetyl-β- It has been shown to be effective in reducing D-glucosaminidase levels, and methods have been disclosed to prevent renal dysfunction by intravenous administration of prostaglandin compounds such as PGE 1 , PGE 2 and PGI 2 (Porter, Am). , 1989, J. Cardiol ., 64: 22E-26E, US Pat. No. 5,807,895). In addition, prostaglandins act as vasodilators that dilate blood vessels in the kidney and are known to cause renal failure when the production of prostaglandins in the kidney is inhibited (Hao. CM, 2008, Annu Rev Physiol, 70, 357-77). ).
따라서 프로스타글란딘을 분해하는 15-PGDH를 억제 또는 저해하는 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체는 신장기능 장애로 인한 신장질환을 예방하거나 또는 치료할 수 있다.  Therefore, the novel thiazolidinedione derivative according to the present invention which inhibits or inhibits 15-PGDH that degrades prostaglandins can prevent or treat kidney disease due to renal dysfunction.
상기에서 신장기능 장애란 정상 크레아티닌이 정제량 미만이거나, 정상 유리수가 정제량 미만이거나, 정상 혈중 우레아 또는 질소 또는 칼륨 또는 크레아티닌의 수치가 정상을 초과하거나, 신장 효소, 예컨대 감마 글루타밀 합성효소, 알라닌 포스파티다제, N-아세틸-β-D-글루코사미니다제 또는 β-2-마이크로글로불린이 변조된 활성을 가지거나, 또는 마크로알부민뇨증이 정상 수치를 초과한 경우 등을 말한다. Renal dysfunction means that the normal creatinine is less than the purified amount, the normal free number is less than the purified amount, the level of normal blood urea or nitrogen or potassium or creatinine is higher than normal, or the kidney enzymes such as gamma glutamyl synthase, alanine force And the case where patidase, N -acetyl-β-D-glucosaminidase, or β-2-microglobulin has modulated activity, or macroalbuminuria exceeds normal levels.
그러므로 본 발명은 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체를 유효성분으로 함유하는 신장질환의 예방 또는 치료용 약학적 조성물을 제공한다. Therefore, the present invention provides a pharmaceutical composition for preventing or treating kidney disease, which contains a novel thiazolidinedione derivative according to the present invention as an active ingredient.
이상 살펴본 바와 같이, 본 발명의 신규한 티아졸리딘디온(thiazolidinedione) 유도체들은 15-PGDH의 저해제로서, 프로스타글란딘의 분해를 억제하는 작용을 통해 탈모를 방지하며 발모를 촉진할 수 있고, 심혈관계 질환, 위장질환 및 신장질환을 치료 또는 예방할 수 있는 효과가 있다. As described above, the novel thiazolidinedione derivatives of the present invention are inhibitors of 15-PGDH, which can prevent hair loss and promote hair growth through the action of inhibiting the decomposition of prostaglandins, cardiovascular diseases, There is an effect that can treat or prevent gastrointestinal diseases and kidney diseases.
한편, PGE1, PGE2 및 PGF2a를 포함하는 프로스타글란딘은 골흡수(bone resorption) 및 골형성(bone formation)을 자극하여 뼈의 부피 및 강도를 증가시키는 작용을 촉진시킨다는 사실이 밝혀진 바 있다(H. Kawaguchi 등, Clinical Orthop. Rel. Res., 313, 1995, 36~46; J. Keller 등, Eur. J. Exp. Musculoskeletal Res.,1, 1992, 8692). 반면, 15-PGDH는 앞서 기술된 바와 같이 프로스타글란딘의 활성을 억제하는 작용이 있다.On the other hand, prostaglandins, including PGE 1 , PGE 2 and PGF2a, have been found to stimulate bone resorption and bone formation to promote the action of increasing bone volume and strength (H. Kawaguchi et al., Clinical Orthop. Rel. Res ., 313, 1995, 36-46; J. Keller et al . , Eur. J. Exp. Musculoskeletal Res., 1, 1992, 8692). 15-PGDH, on the other hand, has the effect of inhibiting the activity of prostaglandins as described above.
따라서 15-PGDH의 활성을 억제할 수 있다면 15-PGDH에 의해 억제된 상기 프로스타글란딘의 작용인 골흡수(bone resorption) 및 골형성(bone formation)을 촉진시킬 수 있다. Therefore, if it is possible to inhibit the activity of 15-PGDH can promote bone resorption and bone formation, the action of the prostaglandin inhibited by 15-PGDH.
그러므로 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체들은 15-PGDH의 활성을 억제할 수 있으므로 골흡수(bone resorption) 및 골형성(bone formation)을 촉진하는 효과를 가질 수 있다. Therefore, the novel thiazolidinedione derivatives according to the present invention may inhibit the activity of 15-PGDH and may have an effect of promoting bone resorption and bone formation.
따라서 본 발명은 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체를 유효성분으로 함유하는 골형성용 조성물을 제공할 수 있다. Therefore, the present invention can provide a composition for bone formation containing a novel thiazolidinedione derivative according to the present invention as an active ingredient.
또한, 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체는 화상을 치료할 수 있는 효과가 있다. In addition, the novel thiazolidinedione derivatives according to the present invention have the effect of treating burns.
프로스타글란딘 중에서 PGE2의 경우, 상처 또는 화상을 치료하는 매개자(meaditor)로의 역할을 하는 것으로 알려져 있다. 그러므로 상처 또는 화상을 치료하는 역할을 하는 PGE2의 활성을 억제하는 15-PGDH를 저해한다면 피부에 상처 또는 화상이 발생하였을 경우 PGE2에 의한 치료효과를 얻을 수 있다.Among prostaglandins, PGE 2 is known to act as a mediator for treating wounds or burns. Therefore, if 15-PGDH inhibits the activity of PGE 2 , which plays a role in treating wounds or burns, it may be possible to obtain a therapeutic effect by PGE 2 when a wound or burn occurs on the skin.
그러므로 본 발명에 따른 신규한 티아졸리딘디온(thiazolidinedione) 유도체는 15-PGDH를 저해하는 활성이 우수하므로 상처 또는 화상을 치료할 수 있기 때문에 본 발명은 상기 신규한 티아졸리딘디온(thiazolidinedione) 유도체를 유효성분으로 함유하는 화상 치료용 조성물을 제공할 수 있다. Therefore, the novel thiazolidinedione derivatives according to the present invention have excellent activity of inhibiting 15-PGDH and thus can be used to treat wounds or burns, so the present invention is effective for the novel thiazolidinedione derivatives. The composition for burn treatment containing as a component can be provided.
상기에서 15-PGDH의 저해제란 특히 인간에 있어 15-PGDH 효소의 활성을 저해 또는 감소시킬 수 있거나, 상기 효소에 의해 촉매되는 반응을 저해, 감소 또는 감속시킬 수 있는 화합물을 말하며, 상기 화학식 1의 유도체를 의미한다.  The inhibitor of 15-PGDH is a compound capable of inhibiting or reducing the activity of 15-PGDH enzyme, or inhibiting, decreasing or slowing the reaction catalyzed by the enzyme, particularly in humans. It means a derivative.
한편, 본 발명에 따른 화학식 1로 표시되는 유도체 화합물을 유효성분으로 함유하는 약학적 조성물은 통상적인 방법에 따라 약학적으로 허용되는 담체 또는 부형제와 혼합하거나 희석제로 희석하여 제조될 수 있다. 또한 상기 약학적 조성물은 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다. 본 발명의 약학적 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화 될 수 있다.  Meanwhile, the pharmaceutical composition containing the derivative compound represented by Formula 1 according to the present invention as an active ingredient may be prepared by mixing with a pharmaceutically acceptable carrier or excipient or diluting with a diluent according to a conventional method. In addition, the pharmaceutical composition may further include fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives. The pharmaceutical compositions of the invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
본 발명의 약학적 조성물은 공지의 방법에 따라 다양한 비경구 또는 경구 투여용 형태로 제조될 수 있는데, 경구투여용 고형제제의 경우, 본 발명의 유도체 화합물에 부형제, 필요에 따라, 결합제, 붕해제, 활제, 착색제, 향미제 및(또는) 교후제를 첨가하고, 얻어진 혼합물을 통상의 방법에 의해 정제, 당의정, 과립제, 산제 또는 캅셀제의 형태로 제조할 수 있다. 첨가제로서는 당분야에 통상 채용되는 것이 사용될 수 있으며, 부형제의 예로서는 유당, 슈크로오즈, 염화나트륨, 글루코오즈, 전분, 탄산칼슘, 카올린, 미세결정 셀룰로오즈 및 규산 등을 들 수 있고, 결합제로서는 물, 에탄올, 프로판올, 단시럽, 슈크로오즈 용액, 전분용액, 젤라틴 용액, 카르복시메틸셀루로오즈, 히드록시프로필 셀루로오즈, 히드록시프로필 스타치, 메틸셀루로오즈, 에틸셀루로오즈, 셸락, 인산칼슘및 폴리피롤리돈을 들 수 있으며, 붕해제로서는 건조전분, 아르긴산나트륨, 한천분말, 중탄산나트륨, 탄산칼슘, 라우릴황산나트륨, 스테아린산모노클리세라이드 및 유당을 들 수 있다. 활제로서는 정제탈크, 스테아레이트류, 붕산나트륨 및 폴리에틸렌 글리콜을 들 수 있고, 향미제로서는 슈크로오즈, 비터 오랜지 피일, 시트르산 및 타르타르산을 들 수 있다. The pharmaceutical compositions of the present invention may be prepared in various parenteral or oral dosage forms according to known methods. In the case of solid dosage forms for oral administration, excipients, if necessary, binders and disintegrants in the derivative compounds of the present invention. , Lubricating agents, coloring agents, flavoring agents, and / or coagulants may be added and the resulting mixture may be prepared in the form of tablets, dragees, granules, powders or capsules by conventional methods. As the additive, those conventionally employed in the art may be used, and examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, and the like. , Propanol, short syrup, sucrose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate And polypyrrolidone. Examples of the disintegrant include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monostearate and lactose. Examples of the lubricant include refined talc, stearates, sodium borate, and polyethylene glycol. Examples of the flavor include sucrose, beater orange oil, citric acid, and tartaric acid.
경구투여용 액제를 제조할 경우, 본 발명의 화합물에 향미제, 완충액, 안정화제, 교후제 등을 가하고, 통상의 방법에 따라 내용제, 시럽제 또는 엘릭서제의 형태로 제조할 수 있다. 완충액의 예로서는 시트르산나트륨을 들 수 있으며, 안정화제의 예로서는 트라가칸트, 아카시아 및 젤라틴을 들 수 있다. 주사제를 제조하기 위해서는 본 발명의 화합물에 pH 조정제, 완충제, 안정화제, 이완제, 국부마취제 등을 가하고 생성혼합물을 피하주사제, 근육주사제 또는 정맥주사제로 할 수 있다. pH 조정제와 완충액으로는 시트르산 나트륨, 아세트산나트륨 및 인산나트륨을 들 수 있다. 안정화제의 예로서는 나트륨피로술파이트, EDTA, 티오글리콜산 및 티오락트산을 들 수 있다. 국부마취제로서는 염산프로카인 및 염산리도카인을 들 수 있으며, 이완제의 예로서는 염화나트륨 및 글루코오즈를 들 수 있다. When preparing a solution for oral administration, flavoring agents, buffers, stabilizers, chemistries, etc. can be added to the compounds of the present invention, and can be prepared in the form of solvents, syrups or elixirs according to conventional methods. Examples of buffers include sodium citrate, and examples of stabilizers include tragacanth, acacia and gelatin. In order to prepare an injection, a pH adjusting agent, a buffer, a stabilizer, a relaxant, a local anesthetic may be added to the compound of the present invention, and the resultant mixture may be a subcutaneous injection, a muscle injection or an intravenous injection. Examples of pH adjusters and buffers include sodium citrate, sodium acetate and sodium phosphate. Examples of stabilizers include sodium pyrosulphite, EDTA, thioglycolic acid, and thioractic acid. Local anesthetics include procaine hydrochloride and lidocaine hydrochloride, and examples of the relaxants include sodium chloride and glucose.
좌제를 제조할 경우, 본 발명의 화합물에 폴리에틸렌글리콜, 라놀린, 카카오버터 또는 지방산 트리글리세라이드와 같은 당분야에 공지된 약학적으로 허용되는 담체와 필요에 따라, 트윈(Tween)과 같은 계면활성화제를 첨가하고, 통상의 방법에 따라 좌제의 형태로 제조할 수 있다. In the preparation of suppositories, the compounds of the present invention may be formulated with pharmaceutically acceptable carriers known in the art, such as polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides, and, if desired, surfactants such as Tween. It can be added and prepared in the form of suppositories according to a conventional method.
연고제를 제조할 경우, 본 발명의 화합물에 연고제를 제조하는데 통상 사용되는 베이스, 안정화제, 보습제, 보존제 등을 첨가하고, 통상의 방법에 따라 연고제로 할 수 있다. 베이스의 예로서는 액상파라핀, 백색 와세린, 백랍, 옥틸도데실알코올 및 파라핀을 들 수 있으며, 보존제로서는 메틸파라옥시벤조에이트, 에틸파라옥시벤조에이트 및 프로필파라옥시벤조에이트를 들 수 있다. When the ointment is prepared, a base, a stabilizer, a moisturizer, a preservative, or the like, which is usually used to prepare an ointment, may be added to the compound of the present invention, and the ointment may be prepared according to a conventional method. Examples of the base include liquid paraffin, white waserine, pewter, octyldodecyl alcohol and paraffin, and preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate and propyl paraoxybenzoate.
상기와 같은 다양한 방법으로 제형화된 약학적 조성물은 약학적으로 유효한 양으로 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있다. Pharmaceutical compositions formulated in various ways as described above may be administered in a pharmaceutically effective amount via a variety of routes including oral, transdermal, subcutaneous, intravenous or intramuscular.
상기에서 약학적으로 유효한 양이란 탈모, 심혈관계 질환, 위장질환 및 신장질환을 개선 또는 치료하기에 충분한 화합물의 양을 말하며, 질환 및 이의 중증정도, 환자의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등에 따라 적절히 변화될 수 있는데, 통상적으로 경구투여의 경우에는 약 1～1000㎎, 주사제의 경우에는 약 0.1～500㎎, 좌제의 경우에는 약 5～1000㎎의 유효용량으로 투여될 수 있다. 상기 제제의 1일 투여량은 환자의 조건, 체중, 연령 및 성별에 따라 다르며, 일괄적으로 제한하여 결정할 수 없다. 통상 1일 투여량은 성인에 대해 약 0.1～5000㎎, 바람직하기로는 약 1～1000㎎이다. 투여는 1일 1회 또는 수차례 분할하여 반복 투여할 수 있다.  The above pharmaceutically effective amount refers to an amount of a compound sufficient to improve or treat hair loss, cardiovascular disease, gastrointestinal disease and kidney disease, and the disease and its severity, age, weight, health condition, sex, and administration of the disease. Depending on the route and duration of treatment, it can be appropriately changed. Usually, it is administered at an effective dose of about 1 to 1000 mg for oral administration, about 0.1 to 500 mg for injection, and about 5 to 1000 mg for suppository. Can be. The daily dosage of the formulation depends on the condition, weight, age and sex of the patient and cannot be determined in a batch. Usually the daily dosage is about 0.1-5000 mg, preferably about 1-1000 mg for adults. Administration can be repeated once or once several times a day.
이하, 본 발명을 실시예에 의해 상세히 설명하기로 한다. 그러나 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail by way of examples. However, these examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited to these examples.
<실시예><Example>
본 발명에 따른 유도체 화합물의 합성Synthesis of Derivative Compounds According to the Invention
하기에 기술된 본 발명에 따른 유도체 화합물의 제조 및 이의 활성를 측정하는 실험에 있어서 사용된 프로스타글란딘(PGE2), NAD+, NADH, 글루타치온 세파로즈 4B, DTT, 소듐 도데실 설페이트(SDS), EDTA 및 환원된 글루타치온은 시그마(Sigma, 미국)로부터 구입하였고, 인간 15-PGDH의 cDNA는 인간 태반 cDNA 라이브러리로부터 클로닝하였다. 또한 UV 스펙트라는 UV-VIS 스펙트라포토미터(Shimadzu 사)를 사용하였고, NMR 스펙트라는 JEOL JNM-LA 300 스펙트로미터(JEOL, 도쿄, 일본)를 사용하였다. Prostaglandins (PGE 2 ), NAD + , NADH, Glutathione Sepharose 4B, DTT, Sodium Dodecyl Sulfate (SDS), EDTA and used in the preparation of the derivative compounds according to the present invention and in the experiments measuring their activity Reduced glutathione was purchased from Sigma, USA, and cDNA of human 15-PGDH was cloned from human placental cDNA library. In addition, UV spectra was used a UV-VIS spectra photometer (Shimadzu Co., Ltd.), NMR spectra was used JEOL JNM-LA 300 spectrometer (JEOL, Tokyo, Japan).
<실시예 1><Example 1>
본 발명에 따른 유도체 1의 제조Preparation of Derivative 1 according to the invention
하기 화학식으로 나타내는 유도체 1을 다음과 같은 방법으로 제조하였다. Derivative 1 represented by the following formula was prepared in the following manner.
<유도체 1의 화학식> <Formula of derivative 1>
Figure PCTKR2009007995-appb-I000006
Figure PCTKR2009007995-appb-I000006
2-이소프로폭시에탄올(600mg, 5.76mmol), p-히드록시벤즈알데히드(0.78g, 6.34 mM) 및 THF(20ml) 중의 트리페닐포스핀(1.6g, 6.1mmol)이 혼합된 용액에 디에틸 아조디카복실레이트(톨루엔 중의 40%)를 0℃에서 10분에 걸쳐 교반하면서 첨가하였다. 이후 상온에서 18시간 동안 2-이소프로폭시에탄올 및 p-히드록시벤즈알데히드의 초기반응물질이 사라질 때까지 교반하였다. 상기 용액을 농축한 다음 실리카 겔을 통한 크로마토그래피를 통해 정제하였으며, 이때 헥산 대 에틸 아세테이트가 5:1이 되는 조건에서 용출시켜 노란색 오일의 4-(2-이소프로폭시에톡시)벤즈알데히드(0.98g, 수율: 82%)를 수득하였다(제1 단계). 상기 수득물의 1H NMR (300MHz, CDCl3) 분석 결과는, δ 9.87(s, 1H), 7.82(d, J=9Hz, 2H), 6.97(d, J=9Hz, 2H), 4.19(t, J=9.9Hz, 2H), 3.81(t, J=10.2Hz, 2H), 3.63-3.75(m, J=24.3Hz, 1H), 1.20(d, J=0.36Hz, 6H)이었다. 이후, 상기 제1 단계에서 수득한 4-(2-이소프로폭시에톡시)벤즈알데히드(0.98g, 4.71mmol) 및 2,4-티아졸리딘디온(0.55g, 4.71mmol)을 20ml의 톨루엔 용액으로 용해시켰고, 여기에 피페리딘(0.23ml, 2.36mmol) 및 아세트산(0.13ml, 2.36mmol)을 순차적으로 첨가한 후, 혼합액을 Dean-Stark 워터 트랩의 환류하에서 밤새도록 가열하였다. 이후 상기 혼합액을 냉각시킨 다음 여과시켰다. 이후 침전물은 에테르 또는 헥산으로 세척한 후 건조시켜 노란색 고체의 상기 화학식으로 표시되는 유도체 1인 5-[4-(2-이소프록시에톡시)벤질리덴]티아졸리딘-2,4-디온(5-(4-(2-Isopropoxyethoxy)benzylidene)thiazolidine-2,4-dione)(1.26g, 수율: 87.5%)을 수득하였다(제2 단계). 상기 유도체 1의 1H NMR (300MHz, CDCl3)은 δ 8.04(s, 1H), 7.805(s, 1H), 7.432(d, J=9Hz, 2H), 7.022(d, J=9Hz, 2H), 4.19(t, J=9.6Hz, 2H), 3.84(t, J=9.6Hz, 2H), 3.65-3.76(m, J=24.6Hz, 1H), 1.24(d, J=6Hz, 6H)이었다.Diethyl azo in a mixture of 2-isopropoxyethanol (600 mg, 5.76 mmol), p-hydroxybenzaldehyde (0.78 g, 6.34 mM) and triphenylphosphine (1.6 g, 6.1 mmol) in THF (20 ml) Dicarboxylate (40% in toluene) was added with stirring at 0 ° C. over 10 minutes. Thereafter, the mixture was stirred for 18 hours at room temperature until the initial reactant of 2-isopropoxyethanol and p-hydroxybenzaldehyde disappeared. The solution was concentrated and purified by chromatography on silica gel, eluting with hexanes to ethyl acetate at 5: 1 to give 4- (2-isopropoxyoxy) benzaldehyde (0.98 g) as a yellow oil. , Yield: 82%) was obtained (first step). The result of 1 H NMR (300 MHz, CDCl 3 ) analysis of the obtained product was δ 9.87 (s, 1 H), 7.82 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 2H), 4.19 (t, J = 9.9 Hz, 2H), 3.81 (t, J = 10.2 Hz, 2H), 3.63-3.75 (m, J = 24.3 Hz, 1H), 1.20 (d, J = 0.36 Hz, 6H). Thereafter, 4- (2-isopropoxyethoxy) benzaldehyde (0.98 g, 4.71 mmol) and 2,4-thiazolidinedione (0.55 g, 4.71 mmol) obtained in the first step were added to 20 ml of toluene solution. After dissolving, piperidine (0.23 ml, 2.36 mmol) and acetic acid (0.13 ml, 2.36 mmol) were added sequentially, followed by heating the mixture overnight under reflux of Dean-Stark water trap. The mixture was then cooled and filtered. The precipitate is then washed with ether or hexane and dried to give 5- [4- (2-isohydroxyethoxy) benzylidene] thiazolidine-2,4-dione as a derivative 1 represented by the above formula as a yellow solid. -(4- (2-Isopropoxyethoxy) benzylidene) thiazolidine-2,4-dione) (1.26 g, yield: 87.5%) was obtained (second step). 1 H NMR of the derivative 1 (300MHz, CDCl 3 ) is δ 8.04 (s, 1H), 7.805 (s, 1H), 7.432 (d, J = 9 Hz, 2H), 7.022 (d, J = 9 Hz, 2H) , 4.19 (t, J = 9.6 Hz, 2H), 3.84 (t, J = 9.6 Hz, 2H), 3.65-3.76 (m, J = 24.6 Hz, 1H), 1.24 (d, J = 6 Hz, 6H). .
<실시예 2><Example 2>
본 발명에 따른 유도체 2의 제조Preparation of Derivative 2 according to the invention
하기 화학식으로 나타내는 유도체 2를 다음과 같은 방법으로 제조하였다. Derivative 2 represented by the following formula was prepared by the following method.
<유도체 2의 화학식> <Formula of derivative 2>
Figure PCTKR2009007995-appb-I000007
Figure PCTKR2009007995-appb-I000007
4-(2-히드록시에틸)모르폴린(1g, 7.62mmol)이 용해되어 있는 건조된 디메틸포름아미드(20ml)용액에 소듐 하이드라이드(201.2mg, 8.38mmol)를 상온의 질소 하에서 천천히 첨가하였다. 상기 혼합물을 상온에서 30분간 교반시켰고, 건조된 디메틸포름아미드(5ml) 중의 4-플루오로벤즈알데히드(1.1g, 8.86mmol)을 10분에 걸쳐 첨가하였다. 반응 혼합물을 상온에서 18시간 동안 초기 반응물질들이 사라질 때 까지 교반하였다. 이후 상기 혼합물에 얼음물을 20ml 첨가한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물로 여러 번 세척한 다음 무수의 황산마그네슘을 이용하여 수분을 제거하고 여과한 다음 용매를 증발시켰다. 잔여 오일은 실리카겔이 충진된 컬럼크로마토그래피를 통해 정제하였으며, 이때 헥산 대 에틸 아세테이트가 5:1이 되는 조건에서 용출시켜 중간체 화합물 4-(2-(모르폴리노에톡시)벤즈알데히드(1.42g, 79%)을 수득하였다. 이때 상기 수득물은 1H NMR (300MHz, CDCl3) δ 10.17(s, 1H), 7.85(d, J=8.7Hz, 2H), 7.00(d, J=8.7Hz, 2H), 4.19(t, J=11.4, 2H), 3.74(t, J=9.0Hz, 4H), 2.83(t, J=11.4, 2H), 2.59(t, J=9Hz, 4H)이었다. 이후 상기 방법으로 제조된 중간체 화합물인 4-(2-(모르폴리노에톡시)벤즈알데히드(1g, 4.3 mmol)와 2,4-티아졸리딘디온(504 mg, 4.3mmol)을 이용하여 상기 실시예 1의 유도체 제조과정 중 제2 단계의 과정을 통해 상기 화학식으로 표시되는 유도체 2인 5-(4-(2-모르폴리노에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Morpholinoethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체의 수율은 90%이며, 1H NMR (300MHz, DMSO-d6)은 δ 8.14(s, 1H), 7.705(s, 1H), 7.544(d, J=8.7Hz, 2H), 7.104(d, J=8.7Hz, 2H), 4.15(t, J=11.4Hz, 2H), 3.57(m, J=9.0Hz, 8H), 2.722(t, J=11.4Hz, 2H)이었다.Sodium hydride (201.2 mg, 8.38 mmol) was slowly added to a dried dimethylformamide (20 ml) solution in which 4- (2-hydroxyethyl) morpholine (1 g, 7.62 mmol) was dissolved under nitrogen at room temperature. The mixture was stirred at room temperature for 30 minutes, and 4-fluorobenzaldehyde (1.1 g, 8.86 mmol) in dried dimethylformamide (5 ml) was added over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours until the initial reactants disappeared. Thereafter, 20 ml of ice water was added to the mixture, followed by extraction with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The remaining oil was purified by silica gel-filled column chromatography, eluting with hexane to ethyl acetate at 5: 1 to give the intermediate compound 4- (2- (morpholinoethoxy) benzaldehyde (1.42 g, 79 %), Wherein the yield was 1 H NMR (300 MHz, CDCl 3 ) δ 10.17 (s, 1 H), 7.85 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H). ), 4.19 (t, J = 11.4, 2H), 3.74 (t, J = 9.0 Hz, 4H), 2.83 (t, J = 11.4, 2H), 2.59 (t, J = 9 Hz, 4H). Example 1 using the 4- (2- (morpholinoethoxy) benzaldehyde (1g, 4.3mmol) and 2,4-thiazolidinedione (504 mg, 4.3mmol) as an intermediate compound prepared by the method 5- (4- (2-morpholinoethoxy) benzylidene) thiazolidine-2,4-dione (5- (4) which is a derivative 2 represented by the above formula through a process of the second step of the derivative manufacturing process. -(2-Morpholinoethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield is 90%, 1 H NMR (300MHz , DMSO-d6) was δ 8.14 (s, 1H), 7.705 (s, 1H), 7.544 (d, J = 8.7Hz, 2H), 7.104 (d, J = 8.7 Hz, 2H), 4.15 (t, J = 11.4 Hz, 2H), 3.57 (m, J = 9.0 Hz, 8H), 2.722 (t, J = 11.4 Hz, 2H).
<실시예 3><Example 3>
본 발명에 따른 유도체 3의 제조Preparation of Derivative 3 according to the invention
하기 화학식으로 나타내는 유도체 3을 다음과 같은 방법으로 제조하였다. Derivative 3 represented by the following formula was prepared in the following manner.
<유도체 3의 화학식> <Formula of derivative 3>
Figure PCTKR2009007995-appb-I000008
Figure PCTKR2009007995-appb-I000008
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-티오펜에탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-티오펜에톡시)벤즈알데히드 화합물을 먼저 수득하였으며, 이때 상기 화합물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.89(s, 1H), 7.85(d, J=10.2Hz, 2H), 7.20(dd, J=1.2, 1.2Hz, 1H), 7.03(d, J=10.2Hz, 2H), 6.92-6.98(m, J=16.2Hz, 2H), 4.30(t, J=12.5Hz, 2H), 3.37(t, J=12.5Hz, 2H)이었다. 이후 상기 수득한 화합물을 상기 실시예 1 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 3인 5-(4-(2-(티오펜-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Thiophen-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.12(s, 1H), 7.73(s, 1H), 7.558(d, J=8.7Hz, 2H), 7.354(dd, J=1.2, 1.2Hz, 1H), 7.12(d, J=8.7Hz, 2H), 6.942-6.973(m, J=9.3Hz, 2H), 4.28(t, J=12.6Hz, 2H), 3.285(t, J=12.5Hz, 2H)이었다.In the process of preparing the derivative of Example 1, except that 2-thiophenethanol is added instead of 2-isopropoxyethanol in the first step to the intermediate 4- (2-thiophene) A methoxy) benzaldehyde compound was first obtained, wherein the yield of the compound was 94%, and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.89 (s, 1H), 7.85 (d, J = 10.2 Hz, 2H), 7.20 (dd, J = 1.2, 1.2 Hz, 1H), 7.03 (d, J = 10.2 Hz, 2H), 6.92-6.98 (m, J = 16.2 Hz, 2H), 4.30 (t, J = 12.5 Hz, 2H) , 3.37 (t, J = 12.5 Hz, 2H). Thereafter, the obtained compound was obtained in the same manner as in Example 2, except that instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step of the derivative manufacturing process, the derivative 3 of Formula 5 -(4- (2- (thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. Yield is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.12 (s, 1H), 7.73 (s, 1H), 7.558 (d, J = 8.7 Hz, 2H), 7.354 (dd, J) = 1.2, 1.2 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.942-6.973 (m, J = 9.3 Hz, 2H), 4.28 (t, J = 12.6 Hz, 2H), 3.285 (t , J = 12.5 Hz, 2H).
<실시예 4><Example 4>
본 발명에 따른 유도체 4의 제조Preparation of Derivative 4 according to the invention
하기 화학식으로 나타내는 유도체 4를 다음과 같은 방법으로 제조하였다. Derivative 4 represented by the following formula was prepared by the following method.
<유도체 4의 화학식> <Formula of derivative 4>
Figure PCTKR2009007995-appb-I000009
Figure PCTKR2009007995-appb-I000009
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 3-티오펜에탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-(티오펜-3-일)에톡시)벤즈알데히드 화합물을 수득하였으며, 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.89(s, 1H), 7.86(d, J=13.8Hz, 2H), 7.03(d, J=13.8Hz, 2H), 4.20(t, J=10.5Hz, 2H), 3.20(dd, J=10.2, 10.2Hz, 8H), 3.04(t, J=10.5Hz, 2H)이었다. 이후 상기 수득한 화합물을 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 4인 5-[4-(2-(티오펜-3-일)에톡시)벤질리덴]티아졸리딘-2,4-디온(5-(4-(2-(Thiophen-3-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.12(s, 1H), 7.69(s, 1H), 7.556(d, J=11.7Hz, 2H), 7.45(d, J=3Hz, 3Hz, 1H), 7.305(s, 1H), 7.11(d, J=11.7Hz, 2H), 4.28(t, J=13.8Hz, 2H), 3.07(t, J=13.8Hz, 2H)이었다.In the process of preparing the derivative of Example 1, except that 3-thiophenethanol was added instead of 2-isopropoxyethanol in the first step, the intermediate 4- (2- (thiophene) was used in the same manner. -3-yl) ethoxy) benzaldehyde compound was obtained, yield 94%, 1 H NMR (300MHz, CDCl 3 ) was δ 9.89 (s, 1H), 7.86 (d, J = 13.8 Hz, 2H), was 7.03 (d, J = 13.8Hz, 2H ), 4.20 (t, J = 10.5Hz, 2H), 3.20 (dd, J = 10.2, 10.2Hz, 8H), 3.04 (t, J = 10.5Hz, 2H) . Thereafter, the obtained compound was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. -[4- (2- (thiophen-3-yl) ethoxy) benzylidene] thiazolidine-2,4-dione (5- (4- (2- (Thiophen-3-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.12 (s, 1H), 7.69 (s, 1H), 7.556 (d, J = 11.7 Hz, 2H), 7.45 (d, J = 3 Hz, 3 Hz, 1H), 7.305 (s, 1H), 7.11 (d, J = 11.7 Hz, 2H), 4.28 (t, J = 13.8 Hz, 2H), 3.07 (t, J = 13.8 Hz, 2H) It was.
<실시예 5>Example 5
본 발명에 따른 유도체 5의 제조Preparation of Derivative 5 According to the Invention
하기 화학식으로 나타내는 유도체 5를 다음과 같은 방법으로 제조하였다. Derivative 5 represented by the following formula was prepared by the following method.
<유도체 5의 화학식> <Formula of derivative 5>
Figure PCTKR2009007995-appb-I000010
Figure PCTKR2009007995-appb-I000010
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-티오모르폴린-1,1-디옥시드에탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-티오모르폴린-1,1-디옥시드에톡시)벤즈알데히드 화합물을 수득하였으며, 수율은 95%이고, 1H NMR (300MHz, CDCl3)은 δ 9.90(s, 1H), 7.87(d, J=13.8Hz, 2H), 7.03(d, J=13.8Hz, 2H), 4.20(t, J=10.5Hz, 2H), 3.20(dd, J=10.2, 10.2Hz, 8H), 3.04(t, J=10.5Hz, 2H)이었다. 이후 상기 수득한 화합물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 5인 5-[4-(2-티오모르폴린-1,1-디옥시드에톡시)벤질리덴]티아졸리딘-2,4-디온(5-[4-(2-Thiomorpholine-1,1-dioxideethoxy)benzylidene]thiazolidine-2,4-dione)을 수득하였다. 이때 수율은 96%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.19(s, 1H), 7.73(s, 1H), 7.56(d, J=8.7Hz, 2H), 7.11(d, J=8.7 Hz, 2H), 4.169(t, J=10.8Hz, 2H), 3.086(dd, J=10.2, 10.2Hz, 8H), 2.945(t, J=10.8Hz, 2H)이었다.In the process of preparing the derivative of Example 1, except that 2-thiomorpholine-1,1-dioxide ethanol is added instead of 2-isopropoxyethanol in the first step, 4- (2-thiomorpholine-1,1-dioxideethoxy) benzaldehyde compound was obtained, yield was 95%, and 1 H NMR (300MHz, CDCl 3 ) was δ 9.90 (s, 1H), 7.87 ( d, J = 13.8Hz, 2H) , 7.03 (d, J = 13.8Hz, 2H), 4.20 (t, J = 10.5Hz, 2H), 3.20 (dd, J = 10.2, 10.2Hz, 8H), 3.04 ( t, J = 10.5 Hz, 2H). Thereafter, the obtained compound represented by the above formula 5 was subjected to the same method, except that the obtained compound was used instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. 5- [4- (2-thiomorpholine-1,1-dioxideethoxy) benzylidene] thiazolidine-2,4-dione (5- [4- (2-Thiomorpholine-1,1-dioxideethoxy) benzylidene] thiazolidine-2,4-dione). Yield is 96%, 1 H NMR (300MHz, DMSO-d6) is δ 8.19 (s, 1H), 7.73 (s, 1H), 7.56 (d, J = 8.7Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H), 4.169 (t, J = 10.8 Hz, 2H), 3.086 (dd, J = 10.2, 10.2 Hz, 8H), 2.945 (t, J = 10.8 Hz, 2H).
<실시예 6><Example 6>
본 발명에 따른 유도체 6의 제조Preparation of Derivative 6 According to the Invention
하기 화학식으로 나타내는 유도체 6을 다음과 같은 방법으로 제조하였다. Derivative 6 represented by the following formula was prepared by the following method.
<유도체 6의 화학식> <Formula of derivative 6>
Figure PCTKR2009007995-appb-I000011
Figure PCTKR2009007995-appb-I000011
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-피리딘에탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 4-(2-(피리딘-2-일)에톡시)벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 85%이고, 1H NMR (300MHz, DMSO-d6)은 δ 9.86(s, 1H), 8.572(d, J=4.5Hz, 1H), 7.834(d, J=8.7Hz, 2H), 7.64(d, J=1.8Hz, 1H), 7.199(m, J=13.2Hz, 1H), 7.278(m, J=4.8Hz, 1H), 7.025(d, J=8.7Hz, 2H), 4.489(t, J=13.5Hz, 2H), 3.32(t, J=13.5Hz, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 6인 5-(4-(2-(피리딘-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Pyridin-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 유도체 6의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 10.36(s, 1H), 8.452(d, J=4.8Hz, 1H), 7.783(s, 1H), 7.719(t, J=17.4Hz, 1H), 7.488(d, J=8.4 Hz, 2H), 7.277(d, J=7.11, 1H), 7.232(m, J=12.6Hz, 1H), 4.169(t, J=14.7Hz, 2H), 3.048(t, J=14.7Hz, 2H)이었다.In the process of preparing the derivative of Example 1, using the same method, except that 2-pyridineethanol was added instead of 2-isopropoxyethanol in the first step, intermediate 4- (2- (pyridine-2- Il) ethoxy) benzaldehyde was obtained, wherein the yield of the product was 85%, 1 H NMR (300MHz, DMSO-d6) was δ 9.86 (s, 1H), 8.572 (d, J = 4.5Hz, 1H) , 7.834 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 1.8 Hz, 1H), 7.199 (m, J = 13.2 Hz, 1H), 7.278 (m, J = 4.8 Hz, 1H), 7.025 (d, J = 8.7 Hz, 2H), 4.489 (t, J = 13.5 Hz, 2H), and 3.32 (t, J = 13.5 Hz, 2H). Subsequently, the derivative 6 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative preparation process of Example 1. Phosphorus 5- (4- (2- (pyridin-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Pyridin-2-yl) ethoxy) benzylidene ) thiazolidine-2,4-dione) was obtained. The yield of the derivative 6 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 10.36 (s, 1H), 8.452 (d, J = 4.8 Hz, 1H), 7.783 (s, 1H), 7.719 (t, J = 17.4 Hz, 1H), 7.488 (d, J = 8.4 Hz, 2H), 7.277 (d, J = 7.11, 1H), 7.232 (m, J = 12.6 Hz, 1H), 4.169 (t, J = 14.7 Hz, 2H) and 3.048 (t, J = 14.7 Hz, 2H).
<실시예 7><Example 7>
본 발명에 따른 유도체 7의 제조Preparation of Derivative 7 According to the Invention
하기 화학식으로 나타내는 유도체 7을 다음과 같은 방법으로 제조하였다. Derivative 7 represented by the following formula was prepared in the following manner.
<유도체 7의 화학식>  <Formula of derivative 7>
Figure PCTKR2009007995-appb-I000012
Figure PCTKR2009007995-appb-I000012
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 N-사이클로헥실에탄올아민을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-사이클로헥실아미노)에톡시벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 79%이고, 1H NMR (300MHz, CDCl3)은 δ 9.81(s, 1H), 7.772 (d, J=8.7Hz, 2H), 6.953(d, J=8.7Hz, 2H), 4.108(t, J=10.5Hz, 2H) 3.013(t, J=10.5Hz, 2H), 2.072(s, 1H). 2.470(m, J=20.4Hz, 1H), 2.072(s, 1H), 1.838-1.148(m, 10H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체를 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 7인5-(4-(2-(사이클로헥실아미노)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Cyclohexylamino)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 유도체 7의 수율은 82%이고, 1H NMR (300MHz, DMSO-d6)은 δ 7.504(d, J=8.7 Hz, 2H), 7.310(s, 1H), 7.069(d, J=8.7Hz, 2H), 4.244 (t, J=9.9Hz, 2H), 3.299(t, J=9.9Hz, 2H), 3.017(s, 1H), 2.284(s, 1H), 2.071(s, 2H) 1.894(s, 2H), 1.61(d, J=11.7Hz), 1.304(m, 5H)이었다.Except for using N -cyclohexylethanolamine instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2, the intermediate was 4- (2-cyclohexylamino, using the same method. Ethoxybenzaldehyde was obtained, wherein the yield of the product was 79%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.81 (s, 1H), 7.772 (d, J = 8.7 Hz, 2H), 6.953 ( d, J = 8.7 Hz, 2H), 4.108 (t, J = 10.5 Hz, 2H) 3.013 (t, J = 10.5 Hz, 2H), 2.072 (s, 1H). 2.470 (m, J = 20.4 Hz, 1H), 2.072 (s, 1H), 1.838-1.148 (m, 10H). The derivative represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation process of the derivative of Example 1. 7-in 5- (4- (2- (cyclohexylamino) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Cyclohexylamino) ethoxy) benzylidene) thiazolidine-2, 4-dione) was obtained. The yield of the derivative 7 is 82%, 1 H NMR (300MHz, DMSO-d6) is δ 7.504 (d, J = 8.7 Hz, 2H), 7.310 (s, 1H), 7.069 (d, J = 8.7 Hz, 2H), 4.244 (t, J = 9.9 Hz, 2H), 3.299 (t, J = 9.9 Hz, 2H), 3.017 (s, 1H), 2.284 (s, 1H), 2.071 (s, 2H) 1.894 (s , 2H), 1.61 (d, J = 11.7 Hz), and 1.304 (m, 5H).
<실시예 8><Example 8>
본 발명에 따른 유도체 8의 제조Preparation of Derivative 8 According to the Invention
하기 화학식으로 나타내는 유도체 7을 다음과 같은 방법으로 제조하였다. Derivative 7 represented by the following formula was prepared in the following manner.
<유도체 8의 화학식> <Formula of derivative 8>
Figure PCTKR2009007995-appb-I000013
Figure PCTKR2009007995-appb-I000013
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용하고 4-플루오로벤즈알데히드 대신 4-플루오로-m-아니스알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 4-(2-사이클로헥실에톡시)-3-메톡시벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.774(s, 1H), 7.383(s, 1H), 7.365(d, J=11.7Hz, 1H), 6.912(d, J=11.7Hz, 1H), 4.096(t, J=9.9Hz, 2H), 3.846(s, 3H), 1.617-1.755(m, 8H), 1.388-1.46(m, 1H), 1.146-1.258(m, 2H), 0.87-0.978(m, 2H)이었다. 이후 상기 수득한 생성물을 상기 실시예 1의 유도체를 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 8인 5-(4-(2-사이클로헥실에톡시)-3-메톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3-methoxybenzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 유도체 8의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.221(s, 1H), 7.728(s, 1H), 7.028(d, J=10.2 Hz, 2H), 6.924(d, J=10.2Hz, 2H), 6.895(s, 1H), 4.074(t, J=14.4 Hz, 2H), 3.846(s, 1H), 1.716(t, J=14.4Hz, 2H), 1.620(m, 1H), 1.434-1.515(m, 4H), 1.078-1.214(m, 4H), 0.867-0.976(m, 2H)이었다.Except for using cyclohexylethanol instead of 4- (2-hydroxyethyl) morpholine in the process of preparing the derivative of Example 2 and 4-fluoro-m-anisaldehyde instead of 4-fluorobenzaldehyde Using the same method, intermediate 4- (2-cyclohexylethoxy) -3-methoxybenzaldehyde was obtained with a yield of 85% and 1 H NMR (300 MHz, CDCl 3 ) yielding δ 9.774 (s , 1H), 7.383 (s, 1H), 7.365 (d, J = 11.7 Hz, 1H), 6.912 (d, J = 11.7 Hz, 1H), 4.096 (t, J = 9.9 Hz, 2H), 3.846 (s , 3H), 1.617-1.755 (m, 8H), 1.388-1.46 (m, 1H), 1.146-1.258 (m, 2H), 0.87-0.978 (m, 2H). Thereafter, the obtained product was subjected to the same method as in the second step of the preparation of the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used in the same manner as the derivative 8 Phosphorus 5- (4- (2-cyclohexylethoxy) -3-methoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3-methoxybenzylidene) thiazolidine-2 , 4-dione) was obtained. The yield of the derivative 8 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 8.221 (s, 1H), 7.728 (s, 1H), 7.028 (d, J = 10.2 Hz, 2H), 6.924 ( d, J = 10.2Hz, 2H) , 6.895 (s, 1H), 4.074 (t, J = 14.4 Hz, 2H), 3.846 (s, 1H), 1.716 (t, J = 14.4Hz, 2H), 1.620 ( m, 1H), 1.434-1.515 (m, 4H), 1.078-1.214 (m, 4H), 0.867-0.976 (m, 2H).
<실시예 9>Example 9
본 발명에 따른 유도체 9의 제조Preparation of Derivative 9 According to the Invention
하기 화학식으로 나타내는 유도체 9를 다음과 같은 방법으로 제조하였다. Derivative 9 represented by the following formula was prepared by the following method.
<유도체 9의 화학식>  <Formula of derivative 9>
Figure PCTKR2009007995-appb-I000014
Figure PCTKR2009007995-appb-I000014
상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 4-히드록시-3-메틸벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 중간체 생성물의 수율은 89%이고, 1H NMR (300MHz, CDCl3)은 δ 9.845(s, 1H), 7.707(d, J=8.7Hz, 2H), 7.678(s, 1H), 6.89(d, J=8.7Hz, 2H), 4.111( t, J=13.2Hz, 2H), 2.259(s, 3H), 1.749(t, J=13.2Hz, 2H) 1.493-1.585(m, 5H), 1.217-1.325(m, 5H),1.009-1.048(m, 1H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시) 벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 9인 5-(4-(2-사이클로헥실에톡시)-3-메틸벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3-methylbenzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 수득한 유도체 9의 수율은 92%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.20(s, 1H), 7.783(s, 1H), 7.087(d, J=8.7 Hz, 2H), 7.058(s, 1H), 6.788(d, J=8.7Hz, 2H), 4.023(t, J=14.7 Hz, 2H), 1.739(t, J=14.7Hz, 2H), 1.577(m, 1H), 1.213-1.284(m, 2H), 0.965-1.044(m, 4H), 0.826-0.880(m, 4H)이었다.Except for using cyclohexylethanol instead of 2-isopropoxyethanol and 4-hydroxy-3-methylbenzaldehyde instead of p-hydroxybenzaldehyde in the preparation of the derivative of Example 1 using the same method An intermediate product was obtained, wherein the yield of the intermediate product was 89%, and 1 H NMR (300 MHz, CDCl 3 ) yields δ 9.845 (s, 1H), 7.707 (d, J = 8.7 Hz, 2H), 7.678 (s , 1H), 6.89 (d, J = 8.7 Hz, 2H), 4.111 (t, J = 13.2 Hz, 2H), 2.259 (s, 3H), 1.749 (t, J = 13.2 Hz, 2H) 1.493-1.585 ( m, 5H), 1.217-1.325 (m, 5H), and 1.009-1.048 (m, 1H). Subsequently, the derivative 9 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (2-cyclohexylethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3-methylbenzylidene) thiazolidine-2, 4-dione) was obtained. The yield of the obtained derivative 9 is 92%, 1 H NMR (300MHz, DMSO-d6) is δ 8.20 (s, 1H), 7.783 (s, 1H), 7.087 (d, J = 8.7 Hz, 2H) , 7.058 (s, 1H), 6.788 (d, J = 8.7 Hz, 2H), 4.023 (t, J = 14.7 Hz, 2H), 1.739 (t, J = 14.7 Hz, 2H), 1.577 (m, 1H) , 1.213-1.284 (m, 2H), 0.965-1.044 (m, 4H) and 0.826-0.880 (m, 4H).
<실시예 10><Example 10>
본 발명에 따른 유도체 10의 제조Preparation of Derivative 10 According to the Invention
하기 화학식으로 나타내는 유도체 10을 다음과 같은 방법으로 제조하였다. Derivative 10 represented by the following formula was prepared in the following manner.
<유도체 10의 화학식> <Formula of derivative 10>
Figure PCTKR2009007995-appb-I000015
Figure PCTKR2009007995-appb-I000015
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 시링알데히드(syringaldehyde)를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 생성물의 수율은 90%이고, 1H NMR (300MHz, CDCl3)은 9.904(s, 1H), 7.273(s, 2H), 4.129(t, J=13.2Hz, 2H), 3.914(s, 6H), 1.646(t, J=13.2Hz, 2H), 1.424-1.781(m, 3H), 1.095-1.169(m, 4H), 0.882-0.989(m, 4H)이었다. 이후 상기 수득한 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 10인 5-(4-(2-사이클로헥실에톡시)-3,5-디메톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3,5-dimethoxybenzylidene)thiazolidine-2,4-dione )을 수득하였다. 상기 수득한 유도체 10의 수율은 92%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.623(s, 1H), 7.781(s, 1H), 6.768(s, 2H), 4.10(t, J=13.5 Hz, 2H), 3.887(s, 6H), 2.176(s, 1H), 1.620(t, J=13.5Hz, 2H), 1.505-1.738(m, 2H), 1.096-1.325(m, 4H), 0.884-0.951(m, 4H)이었다.In the process of preparing the derivative of Example 1, the same method is used except that in the first step, cyclohexyl ethanol is used instead of 2-isopropoxyethanol and siringaldehyde is added instead of p-hydroxybenzaldehyde. To obtain an intermediate product, wherein the yield of the product is 90%, 1 H NMR (300 MHz, CDCl 3 ) is 9.904 (s, 1H), 7.273 (s, 2H), 4.129 (t, J = 13.2 Hz , 2H), 3.914 (s, 6H), 1.646 (t, J = 13.2 Hz, 2H), 1.424-1.781 (m, 3H), 1.095-1.169 (m, 4H), 0.882-0.989 (m, 4H) . Thereafter, the obtained product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that instead of 4- (2-isopropoxyethoxy) benzaldehyde, 5- (4- (2-cyclohexylethoxy) -3,5-dimethoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3,5-dimethoxybenzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 10 is 92%, 1 H NMR (300MHz, DMSO-d6) is δ 8.623 (s, 1H), 7.781 (s, 1H), 6.768 (s, 2H), 4.10 (t, J = 13.5 Hz, 2H), 3.887 (s, 6H), 2.176 (s, 1H), 1.620 (t, J = 13.5 Hz, 2H), 1.505-1.738 (m, 2H), 1.096-1.325 (m, 4H) , 0.884-0.951 (m, 4H).
<실시예 11><Example 11>
본 발명에 따른 유도체 11의 제조Preparation of Derivative 11 According to the Invention
하기 화학식으로 나타내는 유도체 11을 다음과 같은 방법으로 제조하였다. Derivative 11 represented by the following formula was prepared in the following manner.
<유도체 11의 화학식> <Formula of derivative 11>
Figure PCTKR2009007995-appb-I000016
Figure PCTKR2009007995-appb-I000016
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 생성물의 수율은 89%이고, 1H NMR (300MHz, CDCl3)은 δ 9.859(s, 1H), 7.906(s, 1H), 7.759 (d, J=8.4Hz, 2H), 7.034(d, J=8.4Hz, 2H), 4.158(t, J=13.5Hz, 2H), 1.815(t, J=13.5Hz, 2H), 1.698-1.892(m, 2H), 1.483-1.659(m, 1H), 1.184-1.350(m, 4H), 0.896-1.152(m, 4H)이었다. 이후 상기 수득한 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 11인 5-(3-클로로-4-(2-사이클로펙실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 수득한 유도체 11의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.19(s, 1H), 7.738(s, 1H), 7.522(s, 1H)，7.386(d, J=10.5Hz, 1H), 7.012(d, J=10.5Hz, 1H)), 4.155(t, J=13.2Hz, 2H), 1.800(t, J=13.2Hz, 2H), 1.657-1.800(m, 4H), 1.500-1.606(m, 1H), 1.151-1.335(m, 4H), 0.854-1.052(m, 2H)이었다.In the process of preparing the derivative of Example 1, except for using cyclohexyl ethanol instead of 2-isopropoxyethanol in the first step and 3-chloro-4-hydroxybenzaldehyde instead of p-hydroxybenzaldehyde Using the same method to obtain the intermediate product, the yield of the product is 89%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.859 (s, 1H), 7.906 (s, 1H), 7.759 (d , J = 8.4 Hz, 2H), 7.034 (d, J = 8.4 Hz, 2H), 4.158 (t, J = 13.5 Hz, 2H), 1.815 (t, J = 13.5 Hz, 2H), 1.698-1.892 (m , 2H), 1.483-1.659 (m, 1H), 1.184-1.350 (m, 4H), 0.896-1.152 (m, 4H). Thereafter, the obtained product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that instead of 4- (2-isopropoxyethoxy) benzaldehyde, 5- (3-chloro-4- (2-cyclofexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2, 4-dione) was obtained. At this time, the yield of the obtained derivative 11 was 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.19 (s, 1H), 7.738 (s, 1H), 7.522 (s, 1H), 7.386 (d, J = 10.5 Hz, 1H), 7.012 (d, J = 10.5 Hz, 1H)), 4.155 (t, J = 13.2 Hz, 2H), 1.800 (t, J = 13.2 Hz, 2H), 1.657-1.800 (m , 4H), 1.500-1.606 (m, 1H), 1.151-1.335 (m, 4H), 0.854-1.052 (m, 2H).
<실시예 12><Example 12>
본 발명에 따른 유도체 12의 제조Preparation of Derivative 12 According to the Invention
하기 화학식으로 나타내는 유도체 12를 다음과 같은 방법으로 제조하였다. Derivative 12 represented by the following formula was prepared in the following manner.
<유도체 12의 화학식>  <Formula of derivative 12>
Figure PCTKR2009007995-appb-I000017
Figure PCTKR2009007995-appb-I000017
상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 생성물의 수율은 82%이고, 1H NMR (300MHz, CDCl3)은 δ 9.858(s, 1H), 8.271(s, 1H), 7.679(d, J=8.7Hz, 2H), 7.145(d, J=8.7Hz, 2H), 4.118(t, J=13.2Hz, 2H), 4.063(d, J=6.9Hz, 1H), 3.579(t, J=13.8Hz, 4H), 0.762-1.977(m, 10H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 12인 5-(4-(3-사이클로헥실프로폭시)-3-니트로벤질리덴)티아졸리딘-2,4-디온(5-(4-(3-Cyclohexylpropoxy)-3-nitrobenzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 수득한 유도체 12의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.043(s, 1H), 7.716(s, 1H), 7.399(d, J=11.1Hz, 1H), 7.262(s, 1H)，7.041(d, J=11.1Hz, 1H), 4.563(dd, J=12.6, 1H), 4.048-4.087(t, J=11.7Hz, 2H), 4.029-4.179(m, 1H), 1.631-1.889(m, 8H), 1.159-1.389(m, 2H), 1.236-1.284(t, J=14.4Hz, 2H), 0.840-0.961(m, 2H)이었다.Except for using cyclohexylethanol instead of 2-isopropoxyethanol and 3-chloro-4-hydroxybenzaldehyde instead of p-hydroxybenzaldehyde in the preparation of the derivative of Example 1 using the same method An intermediate product was obtained, wherein the yield of the product was 82%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.858 (s, 1H), 8.271 (s, 1H), 7.679 (d, J = 8.7 Hz, 2H), 7.145 (d, J = 8.7 Hz, 2H), 4.118 (t, J = 13.2 Hz, 2H), 4.063 (d, J = 6.9 Hz, 1H), 3.579 (t, J = 13.8 Hz, 4H) , 0.762-1.977 (m, 10H). Thereafter, the derivative 12 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (3-cyclohexylpropoxy) -3-nitrobenzylidene) thiazolidine-2,4-dione (5- (4- (3-Cyclohexylpropoxy) -3-nitrobenzylidene) thiazolidine-2 , 4-dione) was obtained. The yield of the obtained derivative 12 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.043 (s, 1H), 7.716 (s, 1H), 7.399 (d, J = 11.1 Hz, 1H) , 7.262 (s, 1H), 7.041 (d, J = 11.1 Hz, 1H), 4.563 (dd, J = 12.6, 1H), 4.048-4.087 (t, J = 11.7 Hz, 2H), 4.029-4.179 (m , 1H), 1.631-1.889 (m, 8H), 1.159-1.389 (m, 2H), 1.236-1.284 (t, J = 14.4 Hz, 2H) and 0.840-0.961 (m, 2H).
<실시예 13>Example 13
본 발명에 따른 유도체 13의 제조Preparation of Derivative 13 According to the Invention
하기 화학식으로 나타내는 유도체 13을 다음과 같은 방법으로 제조하였다. Derivative 13 represented by the following formula was prepared in the following manner.
<유도체 13의 화학식> <Formula of derivative 13>
Figure PCTKR2009007995-appb-I000018
Figure PCTKR2009007995-appb-I000018
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 4-(2-사이클로헥실에톡시)벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 83%이고, 1H NMR (300MHz, CDCl3)은 δ 9.879(s, 1H), 7.849(d, J=13.8Hz, 2H), 7.014(d, J=13.8Hz, 2H), 4.134(t, J=13.2Hz, 2H), 1.745(t, J=13.2Hz, 2H), 1.474-1.745(m, 6H), 1.047-1.247(m, 3H), 0.875-0.930(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용하고 2,4-치아졸리딘디온 대신 로다닌을 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 13인 5-(4-(2-사이클로헥실에톡시)벤질리덴-4-티옥소티아졸리딘-2-원(5-(4-(2-Cyclohexylethoxy)benzylidene)-4-thioxothiazolidin-2-one)을 수득하였다. 상기 수득한 유도체 13의 수율은 82%이고, 1H NMR (300MHz, DMSO-d6)은 δ 7.758(s, 1H), 7.499(d, J=14.7Hz, 2H), 6.970(d, J=14.7Hz, 2H), 4.036(t, J=11.7Hz, 2H), 3.575(s, 1H), 1.704(t, J=11.7Hz, 2H), 1.565-1.756(m, 5H), 1.434-1.528(m, 1H), 1.103-1.260(m, 3H), 0.907-1.029(m, 2H)이었다. Intermediate 4- (2-cyclohexylethoxy) benzaldehyde was prepared in the same manner, except that cyclohexylethanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. was obtained, wherein a yield of the product was 83%, 1 H NMR (300MHz , CDCl 3) is δ 9.879 (s, 1H), 7.849 (d, J = 13.8Hz, 2H), 7.014 (d, J = 13.8 Hz, 2H), 4.134 (t , J = 13.2Hz, 2H), 1.745 (t, J = 13.2Hz, 2H), 1.474-1.745 (m, 6H), 1.047-1.247 (m, 3H), 0.875-0.930 (m, 2H). The obtained intermediate product was then used in place of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1 and using rhodanine instead of 2,4-thiazolidinedione. And 5- (4- (2-cyclohexylethoxy) benzylidene-4-thioxothiazolidine-2-one (5- (4- (2) which is a derivative 13 represented by the above formula. -Cyclohexylethoxy) benzylidene) -4-thioxothiazolidin-2-one) The yield of the obtained derivative 13 is 82%, 1 H NMR (300MHz, DMSO-d6) is δ 7.758 (s, 1H), 7.499 (d, J = 14.7 Hz, 2H), 6.970 (d, J = 14.7 Hz, 2H), 4.036 (t, J = 11.7 Hz, 2H), 3.575 (s, 1H), 1.704 (t, J = 11.7 Hz 2H), 1.565-1.756 (m, 5H), 1.434-1.528 (m, 1H), 1.103-1.260 (m, 3H), 0.907-1.029 (m, 2H).
<실시예 14><Example 14>
본 발명에 따른 유도체 14의 제조Preparation of Derivative 14 According to the Invention
하기 화학식으로 나타내는 유도체 14를 다음과 같은 방법으로 제조하였다. Derivative 14 represented by the following formula was prepared in the following manner.
<유도체 14의 화학식> <Formula of derivative 14>
Figure PCTKR2009007995-appb-I000019
Figure PCTKR2009007995-appb-I000019
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 1-피페리딘에탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체인 4-(2-피페리딘-1-일)에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 83%이고, 1H NMR (300MHz, CDCl3)은 δ 9.880(s, 1H), 7.839(d, J=8.7Hz, 2H), 7.013(d, J=8.7Hz, 2H), 4.223(t, J=11.7Hz, 2H), 2.828(t, J=11.7Hz, 2H), 2.544(t, J=10.5Hz, 4H), 1.583-1.657(m, 4H), 1.418-1.494(m, 2H), 1.256-1.303(m, 1H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 14인 5-(4-(2-(피페리딘-1-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Piperidin-1-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 14의 수율은 82%이고, 1H NMR (300MHz, DMSO-d6)은 δ 7.522(s, 1H), 7.411(d, J=10.2Hz, 2H), 6.967(d, J=10.2Hz, 2H), 4.096(t, J=11.1Hz, 2H), 2.814(t, J=11.1Hz, 2H), 2.379(m, 4H), 1.410-1.513(m, 5H), 1.291-1.307(m, 2H)이었다.Except for using 1-piperidineethanol instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2 using the same method as the intermediate 4- (2-piperidine -1-yl) ethoxy) benzaldehyde, wherein the yield of the intermediate product is 83%, 1 H NMR (300 MHz, CDCl 3 ) is δ 9.880 (s, 1H), 7.839 (d, J = 8.7Hz , 2H), 7.013 (d, J = 8.7 Hz, 2H), 4.223 (t, J = 11.7 Hz, 2H), 2.828 (t, J = 11.7 Hz, 2H), 2.544 (t, J = 10.5 Hz, 4H ), 1.583-1.657 (m, 4H), 1.418-1.494 (m, 2H), 1.256-1.303 (m, 1H). Subsequently, the derivative 14 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (2- (piperidin-1-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Piperidin-1-yl) ethoxy ) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the resulting derivatives 14 and 82%, 1 H NMR (300MHz, DMSO -d6) is δ 7.522 (s, 1H), 7.411 (d, J = 10.2Hz, 2H), 6.967 (d, J = 10.2 Hz, 2H), 4.096 (t , J = 11.1Hz, 2H), 2.814 (t, J = 11.1Hz, 2H), 2.379 (m, 4H), 1.410-1.513 (m, 5H), 1.291-1.307 (m , 2H).
<실시예 15><Example 15>
본 발명에 따른 유도체 15의 제조Preparation of Derivative 15 According to the Invention
하기 화학식으로 나타내는 유도체 15를 다음과 같은 방법으로 제조하였다. Derivative 15 represented by the following formula was prepared in the following manner.
<유도체 15의 화학식> <Formula of derivative 15>
Figure PCTKR2009007995-appb-I000020
Figure PCTKR2009007995-appb-I000020
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하고 p-히드록시벤즈알데히드 대신 3-브로모-4-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 3-브로모-4-(2-사이클로헥실에톡시)벤즈알데히드를 수득하였으며, 이때 상기 생성물의 수율은 89%이고, 1H NMR (300MHz, CDCl3)은 δ 9.831(s, 1H), 8.077(s, 1H), 7.808(d, J=8.4Hz, 2H), 6.995(d, J=8.4Hz, 2H), 4.223(t, J=14.4Hz, 2H), 1.650-1.811(m, 7H), 1.468-1.627(m, 1H), 1.142-1.296(m, 3H), 0.947-1.111(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 15인 5-(3-브로모-4-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Bromo-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 15의 수율은 90%이고, 1H NMR은 (300MHz, DMSO-d6)은 δ 12.576(s, 1H), 7.841(s, 1H), 7.833(s, 1H)， 7.570(d, J=10.8 Hz, 1H), 7.284(d, J=10.8Hz, 1H), 4.174(t, J=12.6Hz, 2H), 1.617-1.750(m, 7H), 1.460-1.529(m, 1H), 1.062-1.265(m, 3H), 0.896-0.966(m, 2H)이었다.In the process of preparing the derivative of Example 1, except that in the first step using cyclohexyl ethanol instead of 2-isopropoxyethanol and 3-bromo-4-hydroxybenzaldehyde instead of p-hydroxybenzaldehyde And using the same method to obtain the intermediate 3-bromo-4- (2-cyclohexylethoxy) benzaldehyde, where the yield of the product is 89%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.831 (s, 1H), 8.077 (s, 1H), 7.808 (d, J = 8.4 Hz, 2H), 6.995 (d, J = 8.4 Hz, 2H), 4.223 (t, J = 14.4 Hz, 2H), 1.650 -1.811 (m, 7H), 1.468-1.627 (m, 1H), 1.142-1.296 (m, 3H), and 0.947-1.111 (m, 2H). Subsequently, the derivatives represented by the above formulas were subjected to the same method as described above except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (3-bromo-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Bromo-4- (2-cyclohexylethoxy) benzylidene) thiazolidine- 2,4-dione) was obtained. The yield of the obtained derivative 15 is 90%, 1 H NMR is (300MHz, DMSO-d6) is δ 12.576 (s, 1H), 7.841 (s, 1H), 7.833 (s, 1H), 7.570 (d, J = 10.8 Hz, 1H), 7.284 (d, J = 10.8 Hz, 1H), 4.174 (t, J = 12.6 Hz, 2H), 1.617-1.750 (m, 7H), 1.460-1.529 (m, 1H), 1.062-1.265 (m, 3H) and 0.896-0.966 (m, 2H).
<실시예 16><Example 16>
본 발명에 따른 유도체 16의 제조Preparation of Derivative 16 According to the Invention
하기 화학식으로 나타내는 유도체 16을 다음과 같은 방법으로 제조하였다. Derivative 16 represented by the following formula was prepared in the following manner.
<유도체 16의 화학식> <Formula of derivative 16>
Figure PCTKR2009007995-appb-I000021
Figure PCTKR2009007995-appb-I000021
상기 실시예 2의 유도체를 제조하는 과정 중, 제1 단계에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용하고 4-플루오로벤즈알데히드 대신 4-플루오로-3-(트리플루오로메칠)벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 4-(2-사이클로헥실에톡시)-3-(트리플루오로메칠)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 89%이고, 1H NMR (300MHz, CDCl3)은 δ 9.915(s, 1H), 8.102(s, 1H), 8.044(d, J=10.5Hz, 2H), 7.125(d, J=8.7Hz, 2H), 4.208(t, J=12.6Hz, 2H), 1.639-1.788(m, 6H), 1.466-1.567(m, 1H), 1.177-1.338(m, 4H), 0.882-1.041(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 16인 5-(4-(2-사이클로헥실에톡시)-3-트리플루오로메틸)벤질리덴)티아졸리딘-2,4-디온 (5-(4-(2-Cyclohexylethoxy)-3-(trifluoromethyl)benzylidene)thiazolidine-2,4-In the process of preparing the derivative of Example 2, cyclohexylethanol is used instead of 4- (2-hydroxyethyl) morpholine in the first step, and 4-fluoro-3- (trifluoro is used instead of 4-fluorobenzaldehyde. Intermediate 4- (2-cyclohexylethoxy) -3- (trifluoromethyl) benzaldehyde was obtained using the same method except adding locyl) benzaldehyde, where the yield of the intermediate product was 89%. 1 H NMR (300MHz, CDCl 3 ) is δ 9.915 (s, 1H), 8.102 (s, 1H), 8.044 (d, J = 10.5Hz, 2H), 7.125 (d, J = 8.7Hz, 2H) , 4.208 (t, J = 12.6 Hz, 2H), 1.639-1.788 (m, 6H), 1.466-1.567 (m, 1H), 1.177-1.338 (m, 4H), 0.882-1.041 (m, 2H). The derivative represented by the above formula was carried out in the same manner as described above, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative preparation process of Example 1. Phosphorus 5- (4- (2-cyclohexylethoxy) -3-trifluoromethyl) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3- (trifluoromethyl ) benzylidene) thiazolidine-2,4-
dione)을 수득하였다. 상기 수득한 유도체 16의 수율은 92%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.270(s, 1H), 7.812(s, 1H), 7.461(d, J=8.7 Hz, 2H), 7.262(s, 1H), 6.934(d, J=8.7Hz, 2H), 4.080(t, J=13.5Hz, 2H), 1.576-1.738(m, 7H), 1.284-1.506(m, 1H), 1.035-1.245(m, 3H), 0.926-0.995(m, 2H)이었다.dione) was obtained. The yield of the obtained derivative 16 is 92%, 1 H NMR (300MHz, DMSO-d6) is δ 8.270 (s, 1H), 7.812 (s, 1H), 7.461 (d, J = 8.7 Hz, 2H), 7.262 (s, 1H), 6.934 (d, J = 8.7Hz, 2H), 4.080 (t, J = 13.5Hz, 2H), 1.576-1.738 (m, 7H), 1.284-1.506 (m, 1H), 1.035 -1.245 (m, 3H) and 0.926-0.995 (m, 2H).
<실시예 17><Example 17>
본 발명에 따른 유도체 17의 제조Preparation of Derivative 17 According to the Invention
하기 화학식으로 나타내는 유도체 17을 다음과 같은 방법으로 제조하였다. Derivative 17 represented by the following formula was prepared in the following manner.
<유도체 17의 화학식>  <Formula of derivative 17>
Figure PCTKR2009007995-appb-I000022
Figure PCTKR2009007995-appb-I000022
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-(2-하이드록시에틸)티오모르폴린-1,1-디옥사이드를 사용하고 p-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(2-티오모르폴린-1,1-디옥사이드에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 91%이고, 1H NMR (300MHz, CDCl3)은 δ 9.897(s, 1H), 7.70(s, 1H), 7.59(d, J=9.0Hz, 2H), 6.99(d, J=9.0Hz, 2H), 4.14(t, J=10.5Hz, 2H), 3.27(dd, J= 10.2,10.2, 8H), 3.04(t, J=10.5Hz, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 17인 5-[3-클로로-4-(2-티오모르폴린-1,1-디옥시드에톡시)벤질리덴]-티아졸리딘-2,4-디온(5-[3-Chloro-4-(2-thiomorpholine-1,1-dioxideethoxy)benzylidene]-During the preparation of the derivative of Example 1, 4- (2-hydroxyethyl) thiomorpholine-1,1-dioxide instead of 2-isopropoxyethanol in the first step and p-hydroxybenzaldehyde instead Using the same method, except adding 3-chloro-4-hydroxybenzaldehyde, the intermediate product 3-chloro-4- (2-thiomorpholine-1,1-dioxideethoxy) benzaldehyde was obtained. The yield of the intermediate product is 91%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.897 (s, 1H), 7.70 (s, 1H), 7.59 (d, J = 9.0 Hz, 2H), 6.99 ( d, J = was 9.0Hz, 2H), 4.14 (t , J = 10.5Hz, 2H), 3.27 (dd, J = 10.2,10.2, 8H), 3.04 (t, J = 10.5Hz, 2H). Subsequently, the derivative represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- [3-chloro-4- (2-thiomorpholine-1,1-dioxideethoxy) benzylidene] -thiazolidine-2,4-dione (5- [3-Chloro-4- ( 2-thiomorpholine-1,1-dioxideethoxy) benzylidene]-
thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 17의 수율은 94%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.564(s, 1H), 7.724(s, 1H), 7.706(s, 1H), 7.547(d, J=11.1Hz, 2H), 7.11(d, J=9.0Hz, 2H), 4.263(t, J=10.5Hz, 2H), 3.076(s,1H), 2.990(t, J=10.5Hz, 2H)이었다.thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 17 is 94%, 1 H NMR (300MHz, DMSO-d6) is δ 12.564 (s, 1H), 7.724 (s, 1H), 7.706 (s, 1H), 7.547 (d, J) = 11.1 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 4.263 (t, J = 10.5 Hz, 2H), 3.076 (s, 1H), 2.990 (t, J = 10.5 Hz, 2H). .
<실시예 18>Example 18
본 발명에 따른 유도체 18의 제조Preparation of Derivative 18 According to the Invention
하기 화학식으로 나타내는 유도체 18을 다음과 같은 방법으로 제조하였다. Derivative 18 represented by the following formula was prepared in the following manner.
<유도체 18의 화학식> <Formula of derivative 18>
Figure PCTKR2009007995-appb-I000023
Figure PCTKR2009007995-appb-I000023
상기 실시예 2의 유도체를 제조하는 과정 중, 제1 단계에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용하고 4-플루오로벤즈알데히드 대신 2-클로로-4-플루오로벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 2-클로로-4-(2-사이클로헥실에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 89%이고, 1H NMR (300MHz, CDCl3)은 δ 9.447(s, 1H), 7.867(d, J=8.4Hz, 2H), 7.369(s, 1H), 7.043(d, J=8.4Hz, 2H), 4.195(t, J=13.2Hz, 2H), 1.221-1.475(m, 6H), 1.183-1.434(m, 1H), 1.095-1.161(m, 4H), 0.847-0.945(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-2(-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(2-Chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 18을 수득하였다. 상기 수득한 유도체 18의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.654(s, 1H), 7.877(s, 1H), 7.517(d, J=9Hz, 1H), 7.110(s, 1H), 7.012(d, J=9Hz, 1H), 4.111(t, J=13.2Hz, 2H), 1.434-1.642(m, 4H), 1.263-1.434(m, 1H), 1.094-1.221(m, 4H), 0.847-0.989(m, 2H)이었다.In the process of preparing the derivative of Example 2, cyclohexylethanol is used instead of 4- (2-hydroxyethyl) morpholine in the first step, and 2-chloro-4-fluorobenzaldehyde is used instead of 4-fluorobenzaldehyde. The same procedure was followed except for the addition of intermediate 2-chloro-4- (2-cyclohexylethoxy) benzaldehyde, where the yield of the intermediate product was 89%, 1 H NMR (300 MHz, CDCl 3 ) Is δ 9.447 (s, 1H), 7.867 (d, J = 8.4 Hz, 2H), 7.369 (s, 1H), 7.043 (d, J = 8.4 Hz, 2H), 4.195 (t, J = 13.2 Hz, 2H), 1.221-1.475 (m, 6H), 1.183-1.434 (m, 1H), 1.095-1.161 (m, 4H), 0.847-0.945 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. (2-chloro-4-2 (-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (2-Chloro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4- A derivative 18, dione) was obtained. The yield of the obtained derivative 18 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.654 (s, 1H), 7.877 (s, 1H), 7.517 (d, J = 9Hz, 1H), 7.110 (s, 1H), 7.012 (d, J = 9 Hz, 1H), 4.111 (t, J = 13.2 Hz, 2H), 1.434-1.642 (m, 4H), 1.263-1.434 (m, 1H), 1.094-1.221 (m, 4H) and 0.847-0.989 (m, 2H).
<실시예 19>Example 19
본 발명에 따른 유도체 19의 제조Preparation of Derivative 19 According to the Invention
하기 화학식으로 나타내는 유도체 19를 다음과 같은 방법으로 제조하였다. Derivative 19 represented by the following formula was prepared in the following manner.
<유도체 19의 화학식> <Formula of derivative 19>
Figure PCTKR2009007995-appb-I000024
Figure PCTKR2009007995-appb-I000024
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 5-(2-히드록시에칠)-4-메틸티아졸을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 4-(2-(4-메틸티아졸-2-일)에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.89(s, 1H), 8.612(s, 1H), 7.854(d, J=10.2Hz, 2H), 7.014(d, J=10.2Hz, 2H), 4.247(t, J=11.7Hz, 2H), 3.309(t, J=11.7Hz, 2H), 2.463(s, 3H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체의 제조 과정 중, 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-(4-메틸티아졸-5-일)에톡시)벤질리덴-2,4-디온(5-(4-(2-(4-Methylthiazol-5-yl)ethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 19를 수득하였다. 상기 수득한 유도체 19의 수율은 84%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.487(s, 1H), 8.824(s, 1H), 7.721(s, 1H), 7.556(d, J=8.7Hz, 2H), 7.102(d, J=8.7Hz, 1H), 4.238(t, J=12.3Hz, 2H), 3.250(t, J=12.3Hz, 2H), 2.284(s, 3H)이었다.In the process of preparing the derivative of Example 1, the same method was used except that 5- (2-hydroxyethyl) -4-methylthiazole was added instead of 2-isopropoxyethanol in the first step. To obtain 4- (2- (4-methylthiazol-2-yl) ethoxy) benzaldehyde, where the yield of the intermediate product was 94%, and 1 H NMR (300 MHz, CDCl 3 ) was δ. 9.89 (s, 1H), 8.612 (s, 1H), 7.854 (d, J = 10.2 Hz, 2H), 7.014 (d, J = 10.2 Hz, 2H), 4.247 (t, J = 11.7 Hz, 2H), 3.309 (t, J = 11.7 Hz, 2H) and 2.463 (s, 3H). Thereafter, the obtained intermediate product was subjected to the same method as in the preparation of the derivative of Example 1, except that instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step, 5- (4- (2- (4-methylthiazol-5-yl) ethoxy) benzylidene-2,4-dione (5- (4- (2- (4-Methylthiazol-5-yl) ethoxy) Benzylidene) thiazolidine-2,4-dione) was obtained 19. The yield of the obtained derivative 19 was 84%, 1 H NMR (300MHz, DMSO-d6) was δ 12.487 (s, 1H), 8.824 ( s, 1H), 7.721 (s, 1H), 7.556 (d, J = 8.7 Hz, 2H), 7.102 (d, J = 8.7 Hz, 1H), 4.238 (t, J = 12.3 Hz, 2H), 3.250 ( t, J = 12.3 Hz, 2H) and 2.284 (s, 3H).
<실시예 20>Example 20
본 발명에 따른 유도체 20의 제조Preparation of Derivative 20 According to the Invention
하기 화학식으로 나타내는 유도체 20을 다음과 같은 방법으로 제조하였다. Derivative 20 represented by the following formula was prepared in the following manner.
<유도체 20의 화학식>  <Formula of derivative 20>
Figure PCTKR2009007995-appb-I000025
Figure PCTKR2009007995-appb-I000025
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용하고 4-플루오로벤즈알데히드 대신 3,4-디플로로벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로헥실에톡시)-3-플로로벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.857(s, 1H), 7.583-7.633(m, J=15Hz, 2H), 7.087(t, J=15.9Hz, 1H), 4.178(t, J=13.5Hz, 2H), 1.697-1.798(m, 6H), 1.217-1.290(m, 5H), 0.969-1.007(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 20인 5-(4-(2-사이클로헥실에톡시)-3-플루오로벤질리덴-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3-fluorobenzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 20의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.183(s, 1H), 7.610(s, 1H), 7.239(m, 3H)， 4.158(t, J=13.2Hz, 2H), 1.605-1.143(m, 6H), 1.445-1.605(m, 1H), 1.096-1.265(m, 4H), 0.917-0.991(m, 2H)이었다.Except for using the cyclohexyl ethanol instead of 4- (2-hydroxyethyl) morpholine and 3,4-difluorobenzaldehyde instead of 4-fluorobenzaldehyde in the process of preparing the derivative of Example 2 The method was used to obtain the intermediate product 4- (2-cyclohexylethoxy) -3-fluorobenzaldehyde, where the yield of the intermediate product was 85% and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.857. (s, 1H), 7.583-7.633 (m, J = 15 Hz, 2H), 7.087 (t, J = 15.9 Hz, 1H), 4.178 (t, J = 13.5 Hz, 2H), 1.697-1.798 (m, 6H ), 1.217-1.290 (m, 5H), and 0.969-1.007 (m, 2H). Subsequently, the derivative 20 represented by the above formula was carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (2-cyclohexylethoxy) -3-fluorobenzylidene-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3-fluorobenzylidene) thiazolidine-2,4-dione The yield of the obtained derivative 20 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.183 (s, 1H), 7.610 (s, 1H), 7.239 (m, 3H), 4.158 (t, J = 13.2 Hz, 2H), 1.605-1.143 (m, 6H), 1.445-1.605 (m, 1H), 1.096-1.265 (m, 4H), and 0.917-0.991 (m, 2H).
<실시예 21>Example 21
본 발명에 따른 유도체 21의 제조Preparation of Derivative 21 According to the Invention
하기 화학식으로 나타내는 유도체 21을 다음과 같은 방법으로 제조하였다. Derivative 21 represented by the following formula was prepared in the following manner.
<유도체 21의 화학식> <Formula of derivative 21>
Figure PCTKR2009007995-appb-I000026
Figure PCTKR2009007995-appb-I000026
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-(3-히드록시프로필)티오모르폴린-1,1-디옥사이드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(3-티오모르폴린-1,1-디옥사이드프로폭시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 91%이고, 1H NMR (300MHz, CDCl3)은 δ 9.891(s, 1H), 7.865(d, J=11.4Hz, 2H), 7.014(d, J=11.4Hz, 2H), 4.158(t, J=12Hz, 2H), 3.077s, 8H), 2.749(t, J=14.4, 2H), 1.953-2.047(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-(3-티오모르폴린-1,1-디옥사이드프로폭시)벤질리덴]-티아졸리딘-2,4-디온(5-[4-(3-Thiomorpholine-1,1-dioxidepropoxy)benzylidene]-thiazolidine-2,4-In the process of preparing the derivative of Example 1, except that 4- (3-hydroxypropyl) thiomorpholine-1,1-dioxide is added instead of 2-isopropoxyethanol in the first step To obtain the intermediate product 4- (3-thiomorpholine-1,1-dioxidepropoxy) benzaldehyde, the yield of the intermediate product is 91%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.891 (s, 1H), 7.865 (d, J = 11.4 Hz, 2H), 7.014 (d, J = 11.4 Hz, 2H), 4.158 (t, J = 12 Hz, 2H), 3.077 s, 8H), 2.749 ( t, J = 14.4, 2H) and 1.953-2.047 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. [4- (3-thiomorpholine-1,1-dioxidepropoxy) benzylidene] -thiazolidine-2,4-dione (5- [4- (3-Thiomorpholine-1,1-dioxidepropoxy) benzylidene] -thiazolidine-2,4-
dione)인 유도체 21을 수득하였다. 상기 수득한 유도체 21의 수율은 94%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.19(s, 1H), 7.705(s, 1H), 7.540(d, J=8.1 Hz, 2H), 7.088(d, J=8.1Hz, 2H), 4.09(t, J=12Hz, 2H), 3.06(m, 4H), 2.89(m, 4H), 2.616(t, J=14.1Hz, 2H). 1.819-1.911(m, 2H)이었다.A derivative 21, dione) was obtained. The yield of the obtained derivative 21 is 94%, 1 H NMR (300MHz, DMSO-d6) is δ 8.19 (s, 1H), 7.705 (s, 1H), 7.540 (d, J = 8.1 Hz, 2H), 7.088 (d, J = 8.1 Hz, 2H), 4.09 (t, J = 12 Hz, 2H), 3.06 (m, 4H), 2.89 (m, 4H), 2.616 (t, J = 14.1 Hz, 2H). 1.819-1.911 (m, 2H).
<실시예 22><Example 22>
본 발명에 따른 유도체 22의 제조Preparation of Derivative 22 According to the Invention
하기 화학식으로 나타내는 유도체 22를 다음과 같은 방법으로 제조하였다. Derivative 22 represented by the following formula was prepared in the following manner.
<유도체 22의 화학식>  <Formula of derivative 22>
Figure PCTKR2009007995-appb-I000027
Figure PCTKR2009007995-appb-I000027
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-티오핀메탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(티오핀-2-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 89%이고, 1H NMR (300MHz, CDCl3)은 δ 9.893(s, 1H), 7.862(d, J=8.4Hz, 2H), 7.368(d, J=5.1Hz, 1H), 7.153(d, J=3.3Hz, 1H), 7.103(d, J=8.4Hz, 2H), 7.042(t, J=8.4Hz, 1H), 5.309(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(티오펜-2-일메톡시)티아졸리딘-2,4-디온(5-(4-(Thiophen-2-ylmethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 22를 수득하였다. 상기 수득한 유도체 22의 수율은 94%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.513(s, 1H), 7.745(s, 1H), 7.569(d, J=8.4Hz, 2H), 7.559(t, J=2.4Hz, 1H), 7.248(t, J=3.3Hz, 1H), 7.194(d, J=8.4Hz, 2H) 7.052(m, J=10.5Hz, 1H) 5.37(s, 2H)이었다.In the process of preparing the derivative of Example 1, the intermediate product 4- (thioffin-2) was prepared using the same method except that 2-thiopinmethanol was added instead of 2-isopropoxyethanol in the first step. -Ylmethoxy) benzaldehyde, wherein the yield of the intermediate product is 89%, 1 H NMR (300 MHz, CDCl 3 ) is δ 9.893 (s, 1H), 7.862 (d, J = 8.4 Hz, 2H), 7.368 (d, J = 5.1 Hz, 1H), 7.153 (d, J = 3.3 Hz, 1H), 7.103 (d, J = 8.4 Hz, 2H), 7.042 (t, J = 8.4 Hz, 1H), 5.309 ( s, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. A derivative 22 was obtained, which was (4- (thiophen-2-ylmethoxy) thiazolidine-2,4-dione (5- (4- (Thiophen-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione) The yield of the obtained derivative 22 is 94%, 1 H NMR (300MHz, DMSO-d6) is δ 12.513 (s, 1H), 7.745 (s, 1H), 7.569 (d, J = 8.4 Hz, 2H). , 7.559 (t, J = 2.4 Hz, 1H), 7.248 (t, J = 3.3 Hz, 1H), 7.194 (d, J = 8.4 Hz, 2H) 7.052 (m, J = 10.5 Hz, 1H) 5.37 (s , 2H).
<실시예 23><Example 23>
본 발명에 따른 유도체 23의 제조Preparation of Derivative 23 According to the Invention
하기 화학식으로 나타내는 유도체 23을 다음과 같은 방법으로 제조하였다. Derivative 23 represented by the following formula was prepared in the following manner.
<유도체 23의 화학식>  <Formula of derivative 23>
Figure PCTKR2009007995-appb-I000028
Figure PCTKR2009007995-appb-I000028
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 3-티오핀메탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(티오핀-3-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.926(s, 1H), 7.865(d, J=13.8Hz, 2H), 7.350-7.405(m, 2H), 7.164(dd, J=1.5, 1.2Hz, 1H), 5.160(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 23인 5-(4-(티오펜-3-일메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Thiophen-3-ylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 23의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.504(s, 1H), 8.590(s, 1H), 7.864(t, J=17.1Hz, 1H) 7.733(s, 1H), 7.573(d, J=8.7Hz,2H), 7.521(d, J=6Hz, 1H), 7.373(dd, J=5.7, 4.8, 1H), 7.197(d, J=8.7Hz, 2H), 5.252(s, 2H)이었다.In the process of preparing the derivative of Example 1, except that 3-thiopinmethanol was added instead of 2-isopropoxyethanol in the first step, the intermediate product 4- (thioffin-3) was used. -Ylmethoxy) benzaldehyde, where the yield of the intermediate product is 94%, 1 H NMR (300 MHz, CDCl 3 ) is δ 9.926 (s, 1H), 7.865 (d, J = 13.8 Hz, 2H), 7.350-7.405 (m, 2H), 7.164 (dd, J = 1.5, 1.2 Hz, 1H), 5.160 (s, 2H). Subsequently, the derivatives represented by the above formulas were subjected to the same method as described above except that the obtained intermediate product was used instead of 4- (2-isopropoxyoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (thiophen-3-ylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Thiophen-3-ylmethoxy) benzylidene) thiazolidine-2,4-dione) Obtained. The yield of the obtained derivative 23 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.504 (s, 1H), 8.590 (s, 1H), 7.864 (t, J = 17.1 Hz, 1H) 7.733 (s, 1H), 7.573 (d, J = 8.7 Hz, 2H), 7.521 (d, J = 6 Hz, 1H), 7.373 (dd, J = 5.7, 4.8, 1H), 7.197 (d, J = 8.7 Hz , 2H), 5.252 (s, 2H).
<실시예 24><Example 24>
본 발명에 따른 유도체 24의 제조Preparation of Derivative 24 According to the Invention
하기 화학식으로 나타내는 유도체 24를 다음과 같은 방법으로 제조하였다. Derivative 24 represented by the following formula was prepared in the following manner.
<유도체 24의 화학식>  <Formula of derivative 24>
Figure PCTKR2009007995-appb-I000029
Figure PCTKR2009007995-appb-I000029
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로펜틸에탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로펜틸에톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.878(s, 1H), 7.850(d, J=11.4Hz, 2H), 7.014(d, J=11.4Hz, 2H), 4.085(t, J=13.5Hz, 2H), 1.878-2.031(m, 1H), 1.698-1.870(m, 4H), 1.494-1.675(m, 4H), 1.109-1.228(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-사이클로펜틸에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclopentylethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 24를 수득하였다. 상기 수득한 유도체 24의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.502(s, 1H), 7.737(s, 1H), 7.550 (d, J=8.7Hz, 2H), 7.093(d, J=8.7Hz, 2H), 4.136(t, J=13.2Hz, 2H), 2.06(s, 2H), 1.807-1.976(m, 1H), 1.700-1.769(m, 4H), 1.455-1.611(m, 4H), 1.102-1.185(m, 2H)이었다.The intermediate product 4- (2-cyclopentylethoxy) was used in the same manner as in the preparation of the derivative of Example 2, except that cyclopentylethanol was used instead of 4- (2-hydroxyethyl) morpholine. Benzaldehyde was obtained, wherein the yield of the intermediate product was 85%, 1 H NMR (300 MHz, CDCl 3 ) yields δ 9.878 (s, 1H), 7.850 (d, J = 11.4 Hz, 2H), 7.014 (d, J = 11.4 Hz, 2H), 4.085 (t, J = 13.5 Hz, 2H), 1.878-2.031 (m, 1H), 1.698-1.870 (m, 4H), 1.494-1.675 (m, 4H), 1.109-1.228 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. A derivative 24 of (4- (2-cyclopentylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclopentylethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 24 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.502 (s, 1H), 7.737 (s, 1H), 7.550 (d, J = 8.7 Hz, 2H), 7.093 (d, J = 8.7 Hz, 2H), 4.136 (t, J = 13.2 Hz, 2H), 2.06 (s, 2H), 1.807-1.976 (m, 1H), 1.700-1.769 (m, 4H), 1.455 -1.611 (m, 4H) and 1.102-1.185 (m, 2H).
<실시예 25><Example 25>
본 발명에 따른 유도체 25의 제조Preparation of Derivative 25 According to the Invention
하기 화학식으로 나타내는 유도체 25를 다음과 같은 방법으로 제조하였다. Derivative 25 represented by the following formula was prepared in the following manner.
<유도체 25의 화학식>        <Formula of derivative 25>
Figure PCTKR2009007995-appb-I000030
Figure PCTKR2009007995-appb-I000030
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 푸르푸릴 알콜(furfuryl alcohol)을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(퓨란-2-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.895(s, 1H), 7.872(d, J=11.4Hz, 2H), 7.473(s, 1H), 7.118(d, J=11.4Hz, 2H), 6.483(dd, J=3.3, 5.4Hz, 2H), 5.093(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 25인 5-(4-( 퓨란-2-일메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Furan-2-ylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 25의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.518(s, 1H), 7.747(s, 1H), 7.705(s, 1H), 7.572(d, J=8.4Hz, 1H), 7.200(d, J=8.4Hz, 2H), 6.630(dd, J=3, 1.8,1H), 5.142(s, 2H)이었다.In the process of preparing the derivative of Example 1, 4- (furan-, which is an intermediate product, was used in the same manner, except that furfuryl alcohol was added instead of 2-isopropoxyethanol in the first step. 2-ylmethoxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 94%, and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.895 (s, 1H), 7.872 (d, J = 11.4 Hz, 2H). , 7.473 (s, 1H), 7.118 (d, J = 11.4 Hz, 2H), 6.483 (dd, J = 3.3, 5.4 Hz, 2H), and 5.093 (s, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (furan-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Furan-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione) Obtained. The yield of the obtained derivative 25 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.518 (s, 1H), 7.747 (s, 1H), 7.705 (s, 1H), 7.572 (d, J = 8.4 Hz, 1H), 7.200 (d, J = 8.4 Hz, 2H), 6.630 (dd, J = 3, 1.8,1H), 5.142 (s, 2H).
<실시예 26>Example 26
본 발명에 따른 유도체 26의 제조Preparation of Derivative 26 According to the Invention
하기 화학식으로 나타내는 유도체 26을 다음과 같은 방법으로 제조하였다. Derivative 26 represented by the following formula was prepared in the following manner.
<유도체 26의 화학식>  <Formula of derivative 26>
Figure PCTKR2009007995-appb-I000031
Figure PCTKR2009007995-appb-I000031
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 2-피리딘메탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(피리딘-2-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ9.932(s, 1H), 8.630(d, J=4.8Hz, 1H), 7.870(d, J=13.8Hz, 2H), 7.767(t, J=17.1Hz, 1H), 7.513(d, J=7.8Hz, 1H), 7.284 (t, J=12.6Hz, 1H), 7.129(d, J=13.8Hz, 2H), 5.295(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 26인 5-(4-(피리딘-2-일메톡시)벤질리덴)티아졸리딘-2,2-디온(5-(4-(Pyridin-2-ylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 26의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.525(s, 1H), 8.585(d, J=4.2Hz, 1H), 7.865(t, J=16.8Hz, 1H), 7.735(s, 1H), 7.575(d, J=9Hz, 2H), 7.527(d, J=7.8Hz, 1H), 7.372(dd, J=4.8, 4.8, 1H), 7.197(d, J=8.7Hz, 2H), 5.251(s, 2H)이었다.In preparing the derivative of Example 1, 4- (pyridin-2-ylme, which is an intermediate product, was used in the same manner, except that 2-pyridinemethanol was added instead of 2-isopropoxyethanol in the first step. Oxy) benzaldehyde, where the yield of the intermediate product was 94%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.932 (s, 1H), 8.630 (d, J = 4.8 Hz, 1H), 7.870 (d, J = 13.8 Hz, 2H), 7.767 (t, J = 17.1 Hz, 1H), 7.513 (d, J = 7.8 Hz, 1H), 7.284 (t, J = 12.6 Hz, 1H), 7.129 (d , J = 13.8 Hz, 2H), and 5.295 (s, 2H). Subsequently, the derivatives represented by the above formulas were subjected to the same method as described above, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4- (pyridin-2-ylmethoxy) benzylidene) thiazolidine-2,2-dione (5- (4- (Pyridin-2-ylmethoxy) benzylidene) thiazolidine-2,4-dione) Obtained. The yield of the obtained derivative 26 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.525 (s, 1H), 8.585 (d, J = 4.2Hz, 1H), 7.865 (t, J = 16.8 Hz, 1H), 7.735 (s, 1H), 7.575 (d, J = 9 Hz, 2H), 7.527 (d, J = 7.8 Hz, 1H), 7.372 (dd, J = 4.8, 4.8, 1H), 7.197 ( d, J = 8.7 Hz, 2H) and 5.251 (s, 2H).
<실시예 27>Example 27
본 발명에 따른 유도체 27의 제조Preparation of Derivative 27 According to the Invention
하기 화학식으로 나타내는 유도체 27을 다음과 같은 방법으로 제조하였다. Derivative 27 represented by the following formula was prepared in the following manner.
<유도체 27의 화학식> <Formula of derivative 27>
Figure PCTKR2009007995-appb-I000032
Figure PCTKR2009007995-appb-I000032
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-메틸벤질알콜을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-메틸벤질옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.885(s, 1H), 7.891(d, J=11.7Hz, 2H), 7.335(d, J=7.5Hz, 2H), 7.261(d, J=7.5Hz,2H), 7.095(d, J=11.7Hz, 2H), 5.11(s, 2H), 2.371(s, 3H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 27인 5-(4-(4-메틸벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(4-Methylbenzyloxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 27의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.514(s, 1H), 7.800(s, 1H), 7.560(d, J=8.7Hz, 2H), 7.346(d, J=7.8Hz, 2H), 7.206(d, J=8.1Hz, 2H), 7.165(d, J=9Hz, 2H), 5.125(s, 2H), 2.295(s, 3H)이었다.In preparing the derivative of Example 1, 4- (4-methylbenzyl, which is an intermediate product, was used in the same manner, except that 4-methylbenzyl alcohol was added instead of 2-isopropoxyethanol in the first step. Oxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 94%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.885 (s, 1H), 7.891 (d, J = 11.7 Hz, 2H), 7.335 ( d, J = 7.5 Hz, 2H), 7.261 (d, J = 7.5 Hz, 2H), 7.095 (d, J = 11.7 Hz, 2H), 5.11 (s, 2H), 2.371 (s, 3H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (4-methylbenzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (4-Methylbenzyloxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 27 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.514 (s, 1H), 7.800 (s, 1H), 7.560 (d, J = 8.7 Hz, 2H), 7.346 (d, J = 7.8 Hz, 2H), 7.206 (d, J = 8.1 Hz, 2H), 7.165 (d, J = 9 Hz, 2H), 5.125 (s, 2H), 2.295 (s, 3H).
<실시예 28><Example 28>
본 발명에 따른 유도체 28의 제조Preparation of Derivative 28 According to the Invention
하기 화학식으로 나타내는 유도체 28을 다음과 같은 방법으로 제조하였다. Derivative 28 represented by the following formula was prepared in the following manner.
<유도체 28의 화학식> <Formula of derivative 28>
Figure PCTKR2009007995-appb-I000033
Figure PCTKR2009007995-appb-I000033
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-메톡시벤질알콜을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-메톡시벤질옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.889(s, 1H), 7.854(d, J=8.7 Hz, 2H), 7.378(d, J=8.4Hz, 2H), 7.087(d, J=8.7Hz, 2H), 7.095(d, J=9Hz, 2H), 5.077(s, 2H), 3.826(s, 3H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 28인 5-(4-(4-메톡시벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(4-Methoxybenzyloxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 28의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.523(s, 1H), 7.897(s, 1H), 7.470(d, J=8.7Hz, 2H), 7.249(d, J=8.7Hz, 2H), 7.307(d, J=8.4Hz, 2H), 7.165(d, J=8.4Hz, 2H), 5.055(s, 2H), 3,785(s, 3H)이었다.In the process of preparing the derivative of Example 1, except that 4-methoxybenzyl alcohol is added instead of 2-isopropoxyethanol in the first step, the intermediate product 4- (4-meth Oxybenzyloxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 94%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.889 (s, 1H), 7.854 (d, J = 8.7 Hz, 2H), 7.378 (d, J = 8.4 Hz, 2H), 7.087 (d, J = 8.7 Hz, 2H), 7.095 (d, J = 9 Hz, 2H), 5.077 (s, 2H), 3.826 (s, 3H). Subsequently, the derivatives represented by the above formulas were carried out in the same manner, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative preparation process of Example 1 28 Phosphorus 5- (4- (4-methoxybenzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (4-Methoxybenzyloxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 28 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.523 (s, 1H), 7.897 (s, 1H), 7.470 (d, J = 8.7Hz, 2H), 7.249 (d, J = 8.7Hz, 2H), 7.307 (d, J = 8.4Hz, 2H), 7.165 (d, J = 8.4Hz, 2H), 5.055 (s, 2H), 3,785 (s, 3H) .
<실시예 29><Example 29>
본 발명에 따른 유도체 29의 제조Preparation of the derivative 29 according to the invention
하기 화학식으로 나타내는 유도체 29을 다음과 같은 방법으로 제조하였다. Derivative 29 represented by the following formula was prepared in the following manner.
<유도체 29의 화학식> <Formula of derivative 29>
Figure PCTKR2009007995-appb-I000034
Figure PCTKR2009007995-appb-I000034
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 피페로닐알콜을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 5-(4-(벤조[d][1,3]디옥솔-5-일메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.887(s, 1H), 7.861(d, J=13.2 Hz, 2H), 7.084(d, J=13.2Hz, 2H), 6.923(dd, J=1.5, 1.5Hz, 2H), 6.771(s, 1H), 5.98(s, 2H), 5.042(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 29인 5-(4-(벤조[d][1,3]디옥솔-5-일메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Benzo[d][1,3]dioxol-5-ylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 29의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.498(s, 1H), 7.722(s, 1H), 7.558(d, J=9Hz, 2H), 7.157(d, J=8.7Hz, 2H), 7.014(s, 1H), 6.962(dd, J=8.1, 8.1Hz, 2H), 6.011(s, 2H), 5.059(s, 2H)이었다.In the process of preparing the derivative of Example 1, the intermediate product of 5- (4- (benzo [] was used in the same manner, except that piperonyl alcohol was added instead of 2-isopropoxyethanol in the first step. d ] [1,3] dioxol-5-ylmethoxy) benzaldehyde, where the yield of the intermediate product is 94%, 1 H NMR (300 MHz, CDCl 3 ) is δ 9.887 (s, 1H), 7.861 (d, J = 13.2 Hz, 2H), 7.084 (d, J = 13.2Hz, 2H), 6.923 (dd, J = 1.5, 1.5Hz, 2H), 6.771 (s, 1H), 5.98 (s, 2H) And 5.042 (s, 2H) The same procedure was followed except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation process of Example 1. 5- (4- (benzo [ d ] [1,3] dioxol-5-ylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Benzo [ d ] [1,3] dioxol-5-ylmethoxy) benzylidene) thiazolidine-2,4-dione) The yield of the obtained derivative 29 was 89%, and 1 H NMR (300 MHz, DMSO-d 6) was δ 12.498 (s, 1H), 7.722 (s, 1H), 7.558 (d, J = 9Hz, 2H ), 7.157 (d, J = 8.7 Hz, 2H), 7.014 (s, 1H), 6.962 (dd, J = 8.1, 8.1 Hz, 2H), 6.011 (s, 2H), 5.059 (s, 2H).
<실시예 30><Example 30>
본 발명에 따른 유도체 30의 제조Preparation of Derivative 30 According to the Invention
하기 화학식으로 나타내는 유도체 30을 다음과 같은 방법으로 제조하였다. Derivative 30 represented by the following formula was prepared in the following manner.
<유도체 30의 화학식>  <Formula of derivative 30>
Figure PCTKR2009007995-appb-I000035
Figure PCTKR2009007995-appb-I000035
상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 사이클로헥산올을 사용하고 4-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(사이클로헥실옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.834(s, 1H), 7.906(d, J=3.9Hz, 1H), 7.745(dd, J=1.8,2.1Hz, 1H), 7.046(d, J=8.4Hz,1H), 4.443-4.521(m, 1H), 1.943-1.972(m, 2H), 1.825-1.889(m, 2H),1.684-1.803(m, 2H), 1.511-1.673(m, 1H),1.351-1.489(m, 3H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-(사이클로헥실옥시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(cyclohexyloxy)benzylidene)thiazolidine-2,4-dione)인 유도체 30을 수득하였다. 상기 수득한 유도체 30의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.587(s, 1H), 7.724(s, 1H), 7.699(d, J=2.1Hz, 1H), 7.516(dd, J=2.1,2.4Hz, 1H), 7.371(d, J=8.7Hz, 1H), 4.564-4.615(m, 1H), 2.029-2.496(m, 2H), 1.693-1.861(m, 2H), 1.509-1.537(m, 2H), 1.350-1.450(m, 4H)이었다.Except for using cyclohexanol instead of 2-isopropoxyethanol and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde in the preparation of the derivative of Example 1 using the same method Obtaining the intermediate product 3-chloro-4- (cyclohexyloxy) benzaldehyde, the yield of the intermediate product is 85%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.834 (s, 1H), 7.906 (d, J = 3.9 Hz, 1H), 7.745 (dd, J = 1.8,2.1 Hz, 1H), 7.046 (d, J = 8.4 Hz, 1H), 4.443-4.521 (m, 1H), 1.943-1.972 ( m, 2H), 1.825-1.889 (m, 2H), 1.684-1.803 (m, 2H), 1.511-1.673 (m, 1H), 1.351-1.489 (m, 3H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. Derivatives of (3-chloro-4- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione) 30 was obtained. The yield of the obtained derivative 30 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.587 (s, 1H), 7.724 (s, 1H), 7.699 (d, J = 2.1 Hz, 1H), 7.516 (dd, J = 2.1, 2.4 Hz, 1H), 7.371 (d, J = 8.7 Hz, 1H), 4.564-4.615 (m, 1H), 2.029-2.496 (m, 2H), 1.693-1.861 (m, 2H), 1.509-1.537 (m, 2H), 1.350-1.450 (m, 4H).
<실시예 31><Example 31>
본 발명에 따른 유도체 31의 제조Preparation of the derivative 31 according to the invention
하기 화학식으로 나타내는 유도체 31을 다음과 같은 방법으로 제조하였다. Derivative 31 represented by the following formula was prepared in the following manner.
<유도체 31의 화학식> <Formula of derivative 31>
Figure PCTKR2009007995-appb-I000036
Figure PCTKR2009007995-appb-I000036
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실메탄올을사용하고 4-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(사이클로헥실메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.840(s, 1H), 7.900(d, J=2.1Hz, 1H), 7.759(dd, J=1.5, 2.4Hz, 1H), 7.018(d, J=8.4Hz, 1H), 3.914(d, J=5.7Hz, 2H), 1.889-2.046(m, 3H), 1.748-1.862(m, 3H), 1.240-1.424(m, 3H), 1.042-1.231(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-(사이클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 31을 수득하였다. 상기 수득한 유도체 31의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.586(s, 1H), 7.721(s, 1H), 7.697(d, J=2.4Hz, 1H), 7.527(dd, J=2.1, 2.4Hz, 1H), 7.305(d, J=8.7Hz, 1H), 3.949(d, J=6Hz, 2H), 1.626-1.826(m, 6H), 1.034-1.269(m, 5H)이었다.In the process of preparing the derivative of Example 1, except for using cyclohexyl methanol instead of 2-isopropoxyethanol in the first step and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde Using the same method to obtain the intermediate product 3-chloro-4- (cyclohexylmethoxy) benzaldehyde, wherein the yield of the intermediate product is 85%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.840 ( s, 1H), 7.900 (d, J = 2.1 Hz, 1H), 7.759 (dd, J = 1.5, 2.4 Hz, 1H), 7.018 (d, J = 8.4 Hz, 1H), 3.914 (d, J = 5.7 Hz, 2H), 1.889-2.046 (m, 3H), 1.748-1.862 (m, 3H), 1.240-1.424 (m, 3H), 1.042-1.231 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. Derivatives of (3-chloro-4- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione) 31 was obtained. The yield of the obtained derivative 31 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.586 (s, 1H), 7.721 (s, 1H), 7.697 (d, J = 2.4 Hz, 1H), 7.527 (dd, J = 2.1, 2.4 Hz, 1H), 7.305 (d, J = 8.7 Hz, 1H), 3.949 (d, J = 6 Hz, 2H), 1.626-1.826 (m, 6H), 1.034-1.269 ( m, 5H).
<실시예 32><Example 32>
본 발명에 따른 유도체 32의 제조Preparation of the derivative 32 according to the invention
하기 화학식으로 나타내는 유도체 32를 다음과 같은 방법으로 제조하였다. Derivative 32 represented by the following formula was prepared in the following manner.
<유도체 32의 화학식> <Formula of derivative 32>
Figure PCTKR2009007995-appb-I000037
Figure PCTKR2009007995-appb-I000037
상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 3-사이클로헥실-1-프로판올을사용하고 4-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(3-사이클로헥실프로폭시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.843(s, 1H), 7.908(d, J=1.8Hz, 1H), 7.766(d, J=10.5Hz, 1H), 7.026(d, J=8.4Hz, 1H), 4.123(t, J=13.2Hz, 2H), 1.864-1.938(m, 2H), 1.69-1.842(m, 5H), 1.344-1.679(m, 2H), 1.078-1.306(m, 4H), 0.854-0.974(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 32인 5-(3-클로로-4-(3-사이클로헥실프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(3-cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 32의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.587(s, 1H), 7.717(s, 1H), 7.695(d, J=2.1Hz,1H), 7.531(dd, J=2.4, 2.1Hz, 1H), 7.302(d, J=8.4Hz, 1H), 4.125(t, J=12.6Hz, 2H), 1.625-1.772(m, 7H), 1.079-1.348(m, 6H), 0.837-0.911(m, 2H)이었다.Except for using 3-cyclohexyl-1-propanol instead of 2-isopropoxyethanol and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde in the process of preparing the derivative of Example 1 The same method was used to obtain the intermediate product 3-chloro-4- (3-cyclohexylpropoxy) benzaldehyde, wherein the yield of the intermediate product was 85% and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.843. (s, 1H), 7.908 ( d, J = 1.8Hz, 1H), 7.766 (d, J = 10.5Hz, 1H), 7.026 (d, J = 8.4Hz, 1H), 4.123 (t, J = 13.2Hz 2H), 1.864-1.938 (m, 2H), 1.69-1.842 (m, 5H), 1.344-1.679 (m, 2H), 1.078-1.306 (m, 4H), 0.854-0.974 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. Phosphorus 5- (3-chloro-4- (3-cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (3-cyclohexylpropoxy) benzylidene) thiazolidine-2 , 4-dione) was obtained. The yield of the obtained derivative 32 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.587 (s, 1H), 7.717 (s, 1H), 7.695 (d, J = 2.1 Hz, 1H), 7.531 (dd, J = 2.4, 2.1 Hz, 1H), 7.302 (d, J = 8.4 Hz, 1H), 4.125 (t, J = 12.6 Hz, 2H), 1.625-1.772 (m, 7H), 1.079-1.348 (m, 6H) and 0.837-0.911 (m, 2H).
<실시예 33><Example 33>
본 발명에 따른 유도체 33의 제조Preparation of the derivative 33 according to the invention
하기 화학식으로 나타내는 유도체 33을 다음과 같은 방법으로 제조하였다. Derivative 33 represented by the following formula was prepared in the following manner.
<유도체 33의 화학식> <Formula of derivative 33>
Figure PCTKR2009007995-appb-I000038
Figure PCTKR2009007995-appb-I000038
상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 4-사이클로헥실-1-부탄올을사용하고 4-히드록시벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(4-사이클로헥실부톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.842 (s, 1H), 7.905 (t, J=5.4Hz, 1H), 7.764(dd, J=1.8, 2.7Hz, 1H), 7.029(d, J=11.7Hz, 1H), 4.136(t, J=12.6, 2H), 1.830-1.903(m, 2H), 1.679-1.809(m, 6H), 1.461-1.675(m, 2H), 1.112-1.294(m, 7H), 0.859-0.93(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 33인 5-(3-클로로-4-(4-사이클로헥실부톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Chloro-4-(4-cyclohexylbutoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 33의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.582(s, 1H), 7.730(s, 1H), 7.695(d, J=2.1Hz, 1H), 7.532 (dd, J=2.1, 2.1Hz, 1H), 7.309(d, J=9Hz, 1H), 4.141(t, J=12.3Hz, 2H), 1.652-1.761(m, 7H), 1.227-1.615(m, 2H), 1.067-1.205(m, 6H), 0.818-0.889(m, 2H)이었다.Except for using 4-cyclohexyl-1-butanol instead of 2-isopropoxyethanol and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde in the preparation of the derivative of Example 1 The same method was used to yield the intermediate product 3-chloro-4- (4-cyclohexylbutoxy) benzaldehyde, wherein the yield of the intermediate product was 85% and 1 H NMR (300 MHz, CDCl 3 ) was δ 9.842. (s, 1H), 7.905 (t, J = 5.4 Hz, 1H), 7.764 (dd, J = 1.8, 2.7 Hz, 1H), 7.029 (d, J = 11.7 Hz, 1H), 4.136 (t, J = 12.6, 2H), 1.830-1.903 (m, 2H), 1.679-1.809 (m, 6H), 1.461-1.675 (m, 2H), 1.112-1.294 (m, 7H), 0.859-0.93 (m, 2H). . Thereafter, the obtained intermediate product was subjected to the same method as in Example 2, except that 4- (2-isopropoxyethoxy) benzaldehyde was used instead of 4- (2-isopropoxyethoxy) benzaldehyde. 5- (3-chloro-4- (4-cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Chloro-4- (4-cyclohexylbutoxy) benzylidene) thiazolidine-2, 4-dione) was obtained. The yield of the obtained derivative 33 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.582 (s, 1H), 7.730 (s, 1H), 7.695 (d, J = 2.1 Hz, 1H), 7.532 (dd, J = 2.1, 2.1 Hz, 1H), 7.309 (d, J = 9 Hz, 1H), 4.141 (t, J = 12.3 Hz, 2H), 1.652-1.761 (m, 7H), 1.227-1.615 ( m, 2H), 1.067-1.205 (m, 6H) and 0.818-0.889 (m, 2H).
<실시예 34><Example 34>
본 발명에 따른 유도체 34의 제조Preparation of Derivative 34 According to the Invention
하기 화학식으로 나타내는 유도체 34를 다음과 같은 방법으로 제조하였다. Derivative 34 represented by the following formula was prepared in the following manner.
<유도체 34의 화학식>  <Formula of derivative 34>
Figure PCTKR2009007995-appb-I000039
Figure PCTKR2009007995-appb-I000039
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 사이클로헥실에탄올을 사용하였고, 4-히드록시벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드를 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물을 수득하였으며, 이때 상기 중간체 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 10.532 (s, 1H), 7.582(dd, J=2.7, 2.7Hz, 1H), 7.205-7.339(m, 1H), 7.162(dd, J=1.5, 1.5Hz, 1H), 4.125(t, J=13.2Hz, 2H), 1.645-1.804(m, 6H), 1.389-1.593(m, 1H), 1.118-1.339(m, 4H), 0.854-1.055(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 34인 5-(2-클로로-3-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,-4-디온(5-(2-Chloro-3-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 34의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.582(s, 1H), 7.908(s, 1H), 7.462(t, J=15.9Hz, 1H), 7.283(d, J=8.4Hz, 1H), 7.150(d, J=7.8Hz, 1H), 4.140(t, J=12.9Hz, 2H), 1.642-1.758(m, 7H), 1.493(m, 1H), 1.161-1.228(m, 3H), 0.933-0.969(m, 2H)이었다.In the process of preparing the derivative of Example 1, cyclohexylethanol was used instead of 2-isopropoxyethanol in the first step, except that 2-chloro-3-hydroxybenzaldehyde was added instead of 4-hydroxybenzaldehyde. Using the same method to obtain an intermediate product, the yield of the intermediate product is 85%, 1 H NMR (300MHz, CDCl 3 ) is δ 10.532 (s, 1H), 7.582 (dd, J = 2.7, 2.7 Hz, 1H), 7.205-7.339 (m, 1H), 7.162 (dd, J = 1.5, 1.5 Hz, 1H), 4.125 (t, J = 13.2 Hz, 2H), 1.645-1.804 (m, 6H), 1.389-1.593 (m, 1H), 1.118-1.339 (m, 4H) and 0.854-1.055 (m, 2H). Thereafter, the derivative was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (2-chloro-3- (2-cyclohexylethoxy) benzylidene) thiazolidine-2, -4-dione (5- (2-Chloro-3- (2-cyclohexylethoxy) benzylidene) thiazolidine- 2,4-dione) was obtained. The yield of the obtained derivative 34 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.582 (s, 1H), 7.908 (s, 1H), 7.462 (t, J = 15.9 Hz, 1H), 7.283 (d, J = 8.4 Hz, 1H), 7.150 (d, J = 7.8 Hz, 1H), 4.140 (t, J = 12.9 Hz, 2H), 1.642-1.758 (m, 7H), 1.493 (m, 1H ), 1.161-1.228 (m, 3H), and 0.933-0.969 (m, 2H).
<실시예 35><Example 35>
본 발명에 따른 유도체 35의 제조Preparation of Derivative 35 According to the Invention
하기 화학식으로 나타내는 유도체 35를 다음과 같은 방법으로 제조하였다. Derivative 35 represented by the following formula was prepared in the following manner.
<유도체 35의 화학식> <Formula of derivative 35>
Figure PCTKR2009007995-appb-I000040
Figure PCTKR2009007995-appb-I000040
상기 실시예 1의 유도체를 제조하는 과정에서 2-이소프로폭시에탄올 대신 사이클로펜틸메탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(사이클로펜틸메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.878(s, 1H), 7.848 (d, J=11.4Hz, 2H), 7.018(d, J=11.4Hz, 2H), 3.928(d, J=7.2Hz, 2H), 2.340-2.439(m, 1H), 1.822-1.911(m, 2H), 1.581-1.808(m, 4H), 1.312-1.424(m, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 35인 5-(4-(사이클로펜틸메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Cyclopentylmethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 35의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.503(s, 1H), 7.732(s, 1H), 7.547(d, J=9Hz, 2H), 7.094(d, J=9Hz, 2H), 3.922(d, J=7.2Hz, 2H), 2.253-2.351(m, 1H), 1.750-1.770(m, 2H), 1.525-1.603(m, 4H), 1.283-1.344(m, 2H)이었다.The intermediate product 4- (cyclopentylmethoxy) benzaldehyde was obtained by the same method except that cyclopentylmethanol was used instead of 2-isopropoxyethanol in the preparation of the derivative of Example 1, wherein The yield of the intermediate product is 85%, 1 H NMR (300 MHz, CDCl 3 ) is δ 9.878 (s, 1 H), 7.848 (d, J = 11.4 Hz, 2H), 7.018 (d, J = 11.4 Hz, 2H) , 3.928 (d, J = 7.2 Hz, 2H), 2.340-2.439 (m, 1H), 1.822-1.911 (m, 2H), 1.581-1.808 (m, 4H), 1.312-1.424 (m, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (cyclopentylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Cyclopentylmethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 35 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 12.503 (s, 1H), 7.732 (s, 1H), 7.547 (d, J = 9Hz, 2H), 7.094 (d, J = 9 Hz, 2H), 3.922 (d, J = 7.2 Hz, 2H), 2.253-2.351 (m, 1H), 1.750-1.770 (m, 2H), 1.525-1.603 (m, 4H), 1.283 -1.344 (m, 2H).
<실시예 36><Example 36>
본 발명에 따른 유도체 36의 제조Preparation of the derivative 36 according to the invention
하기 화학식으로 나타내는 유도체 36을 다음과 같은 방법으로 제조하였다. Derivative 36 represented by the following formula was prepared in the following manner.
<유도체 36의 화학식> <Formula of derivative 36>
Figure PCTKR2009007995-appb-I000041
Figure PCTKR2009007995-appb-I000041
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-(클로로메틸)벤질알콜을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-클로로메틸벤질옥시)벤즈알데히드를 수득하였으며, 상기 중간체 생성물의 수율은 94%이고, 1H NMR (300MHz, CDCl3)은 δ 9.932(s, 1H), 7.87(d, J=14.4 Hz, 2H), 7.433(s, 4H), 7.096(d, J=13.8Hz, 2H), 5.157(s, 2H), 4.605(s, 2H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체의 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(4-(클로로메틸)벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(4-(Chloromethyl)benzyloxy)benzylidene)thiazolidine-2,4-dione)인 유도체 36을 수득하였다. 상기 수득한 유도체 36의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.549(s, 1H), 7.748(s, 1H), 7.58(dd, J=3.3,3.0Hz, 4H), 7.454(s, 2H) 7.190(dd, J=3.9,3.9Hz, 2H), 5.219(s, 2H), 4.760(s, 2H)이었다.In the process of preparing the derivative of Example 1, 4- (4), which is an intermediate product, was used in the same manner, except that 4- (chloromethyl) benzyl alcohol was added instead of 2-isopropoxyethanol in the first step. -Chloromethylbenzyloxy) benzaldehyde was obtained, yield of the intermediate product was 94%, 1 H NMR (300 MHz, CDCl 3 ) was δ 9.932 (s, 1H), 7.87 (d, J = 14.4 Hz, 2H) , 7.433 (s, 4H), 7.096 (d, J = 13.8 Hz, 2H), 5.157 (s, 2H), and 4.605 (s, 2H). Thereafter, the obtained intermediate product was subjected to the same method as in Formula 2, except that the intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation of the derivative of Example 1. -(4- (4- (chloromethyl) benzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (4- (Chloromethyl) benzyloxy) benzylidene) thiazolidine-2,4-dione) Phosphorus derivative 36 was obtained. The yield of the obtained derivative 36 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.549 (s, 1H), 7.748 (s, 1H), 7.58 (dd, J = 3.3, 3.0 Hz, 4H ), 7.454 (s, 2H), 7.190 (dd, J = 3.9,3.9 Hz, 2H), 5.219 (s, 2H), 4.760 (s, 2H).
<실시예 37><Example 37>
본 발명에 따른 유도체 37의 제조Preparation of the derivative 37 according to the invention
하기 화학식으로 나타내는 유도체 37을 다음과 같은 방법으로 제조하였다. Derivative 37 represented by the following formula was prepared in the following manner.
<유도체 37의 화학식> <Formula of derivative 37>
Figure PCTKR2009007995-appb-I000042
Figure PCTKR2009007995-appb-I000042
상기 실시예 1의 유도체를 제조하는 과정 중, 제1 단계에서 2-이소프로폭시에탄올 대신 4-메틸사이클로헥실메탄올을 첨가하는 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-메틸사이클로헥실메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이고, 상기 생성물의 1H NMR (300MHz, CDCl3)은 δ 9.371(s, 1H), 7.378(d, J=8.7Hz, 2H), 6.66(d, J=8.7Hz, 2H), 3.531(d, J=7.2Hz,1H), 3.419(d, J=6.6Hz, 1H), 1.19-1.499(m, 3H), 0.943-1.047(m, 4H), 0.64-0.821(m, 2H), 0.375-0.596(m, 4H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 37인 5-(4-((메틸사이클로헥실)메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-((4-Methylcyclohexyl)methoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 37의 수율은 89%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.493(s, 1H), 7.693(s, 1H), 7.536(d, J=9.0Hz, 2H), 7.101(dd, J=6.9,6.9Hz, 2H), 3.963(d, J=6.9Hz, 1H), 3.851(d, J=6.6Hz, 1H), 1.662-1.976(m, 4H), 1.185-1.516(m, 4H), 0.975-1.161(m, 2H), 0.852-0.935(m, 3H)이었다.In preparing the derivative of Example 1, 4- (4-methyl as an intermediate product, using the same method, except that 4-methylcyclohexylmethanol was added instead of 2-isopropoxyethanol in the first step. Cyclohexylmethoxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 94%, and the 1 H NMR (300 MHz, CDCl 3 ) of the product was δ 9.371 (s, 1H), 7.378 (d, J = 8.7 Hz , 2H), 6.66 (d, J = 8.7 Hz, 2H), 3.531 (d, J = 7.2 Hz, 1H), 3.419 (d, J = 6.6 Hz, 1H), 1.19-1.499 (m, 3H), 0.943 -1.047 (m, 4H), 0.64-0.821 (m, 2H), and 0.375-0.596 (m, 4H). Subsequently, the derivatives represented by the above formulas were subjected to the same method as described above except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4-((methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4-dione (5- (4-((4-Methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4-dione ) Was obtained. The yield of the obtained derivative 37 is 89%, 1 H NMR (300MHz, DMSO-d6) is δ 12.493 (s, 1H), 7.693 (s, 1H), 7.536 (d, J = 9.0 Hz, 2H), 7.101 (dd, J = 6.9,6.9 Hz, 2H), 3.963 (d, J = 6.9 Hz, 1H), 3.851 (d, J = 6.6 Hz, 1H), 1.662-1.976 (m, 4H), 1.185-1.516 (m, 4H), 0.975-1.161 (m, 2H) and 0.852-0.935 (m, 3H).
<실시예 38>      <Example 38>
본 발명에 따른 유도체 38의 제조Preparation of the derivative 38 according to the invention
하기 화학식으로 나타내는 유도체 38을 다음과 같은 방법으로 제조하였다.       Derivative 38 represented by the following formula was prepared in the following manner.
<유도체 38의 화학식>       <Formula of derivative 38>
Figure PCTKR2009007995-appb-I000043
Figure PCTKR2009007995-appb-I000043
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 2-(테트라히드로-2H-피란-2-일)메탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-(테트라히드로-2H-피란-2-일)메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 90%이고, 상기 생성물의 1H NMR (300MHz, CDCl3)은 δ 9.881(s, 1H), 7.839(d, J=14.1Hz, 2H), 7.044(d, J=14.1Hz, 2H), 4.034-4.087(m, 2H), 3.943-3.990(m, 1H), 3.703-3.780(m, 1H), 3.481-3.566(m, 1H), 1.908-1.948(m, 1H), 1.451-1.692(m, 5H)이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 38인 5-(4-(2-(테트라히드로-2H-퓨란-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Tetrahydro-2H-pyran-2-yl)ethoxy)benzylidene)thiazolidine-2,4-Except for using 2- (tetrahydro-2 H -pyran-2-yl) methanol instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2 using the same method Obtaining the intermediate product 4- (2- (tetrahydro-2 H -pyran-2-yl) methoxy) benzaldehyde, the yield of the intermediate product is 90%, the 1 H NMR of the product (300MHz, CDCl 3 ) is δ 9.881 (s, 1H), 7.839 (d, J = 14.1 Hz, 2H), 7.044 (d, J = 14.1 Hz, 2H), 4.034-4.087 (m, 2H), 3.943-3.990 (m, 1H), 3.703-3.780 (m, 1H), 3.481-3.566 (m, 1H), 1.908-1.948 (m, 1H), 1.451-1.692 (m, 5H). Thereafter, the obtained intermediate product was subjected to the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. Phosphorus 5- (4- (2- (tetrahydro- 2H -furan-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Tetrahydro-2 H -pyran-2-yl) ethoxy) benzylidene) thiazolidine-2,4-
dione)을 수득하였다. 상기 수득한 유도체 38의 수율은 93%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.290(s, 1H), 7.726 (s, 1H), 7.545(d, J=9.0Hz, 2H), 3.978(d, J=5.1Hz, 2H), 3.850-3.892(m, 2H), 3.595-3.638(m, 1H), 1.974-2.119(m, 4H), 1.601-1.858(m, 2H), 1.279-1.470(m, 2H)이었다.dione) was obtained. The yield of the obtained derivative 38 is 93%, 1 H NMR (300MHz, DMSO-d6) is δ 8.290 (s, 1H), 7.726 (s, 1H), 7.545 (d, J = 9.0 Hz, 2H), 3.978 (d, J = 5.1 Hz, 2H), 3.850-3.892 (m, 2H), 3.595-3.638 (m, 1H), 1.974-2.119 (m, 4H), 1.601-1.858 (m, 2H), 1.279- 1.470 (m, 2 H).
<실시예 39>       <Example 39>
본 발명에 따른 유도체 39의 제조Preparation of the derivative 39 according to the invention
하기 화학식으로 나타내는 유도체 39를 다음과 같은 방법으로 제조하였다.      Derivative 39 represented by the following formula was prepared in the following manner.
<유도체 39의 화학식>       <Formula of derivative 39>
Figure PCTKR2009007995-appb-I000044
Figure PCTKR2009007995-appb-I000044
4-히드록시벤즈알데히드를 상기 실시예 1 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 39인 5-(4-히드록시벤질리덴)티아졸리딘-2,4-디온(5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 유도체 39의 수율은 94%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.411(s, 1H), 10.313(s, 1H), 7.971(s, 1H), 7.459(d, J=9.0Hz, 2H), 6.914(d, J=9.0 Hz, 2H)이었다.Except that 4-hydroxybenzaldehyde was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation of the derivative of Example 1, the derivative 39 represented by the formula -(4-hydroxybenzylidene) thiazolidine-2,4-dione (5- (4-Hydroxybenzylidene) thiazolidine-2,4-dione) was obtained. The yield of the derivative 39 is 94%, 1 H NMR (300MHz, DMSO-d6) is δ 12.411 (s, 1H), 10.313 (s, 1H), 7.971 (s, 1H), 7.459 (d, J = 9.0 Hz, 2H), 6.914 (d, J = 9.0 Hz, 2H).
<실시예 40>      <Example 40>
본 발명에 따른 유도체 40의 제조Preparation of Derivative 40 According to the Invention
하기 화학식으로 나타내는 유도체 40을 다음과 같은 방법으로 제조하였다.      Derivative 40 represented by the following formula was prepared in the following manner.
<유도체 40의 화학식>       <Formula of derivative 40>
Figure PCTKR2009007995-appb-I000045
Figure PCTKR2009007995-appb-I000045
4-메톡시벤즈알데히드를 상기 실시예 1 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 40인 5-(4-메톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-Methoxybenzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 유도체 40의 수율은 86%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.411(s, 1H), 10.313(s, 1H), 7.971(s, 1H), 7.459(d, J=9.0Hz, 2H), 6.914(d, J=9.0 Hz, 2H)이었다.Except that 4-methoxybenzaldehyde was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation of the derivative of Example 1, the derivative 40 represented by the formula -(4-methoxybenzylidene) thiazolidine-2,4-dione (5- (4-Methoxybenzylidene) thiazolidine-2,4-dione) was obtained. The yield of the derivative 40 is 86%, 1 H NMR (300MHz, DMSO-d6) is δ 12.411 (s, 1H), 10.313 (s, 1H), 7.971 (s, 1H), 7.459 (d, J = 9.0 Hz, 2H), 6.914 (d, J = 9.0 Hz, 2H).
<실시예 41>      <Example 41>
본 발명에 따른 유도체 41의 제조Preparation of the derivative 41 according to the invention
하기 화학식으로 나타내는 유도체 41을 다음과 같은 방법으로 제조하였다.       Derivative 41 represented by the following formula was prepared in the following manner.
<유도체 41의 화학식>       <Formula of derivative 41>
Figure PCTKR2009007995-appb-I000046
Figure PCTKR2009007995-appb-I000046
4-에톡시벤즈알데히드를 상기 실시예 1 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 41인 5-(4-에톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-Ethoxybenzylidene)thiazolidine-2,4-dione)을 수득하였다. 이때 상기 유도체 41의 수율은 91%이었다. Except for using 4-ethoxybenzaldehyde instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the preparation of the derivative of Example 1, the derivative 41 represented by the above formula 5 -(4-ethoxybenzylidene) thiazolidine-2,4-dione (5- (4-Ethoxybenzylidene) thiazolidine-2,4-dione) was obtained. At this time, the yield of the derivative 41 was 91%.
<실시예 42>      <Example 42>
본 발명에 따른 유도체 42의 제조Preparation of Derivative 42 According to the Invention
하기 화학식으로 나타내는 유도체 42를 다음과 같은 방법으로 제조하였다.      Derivative 42 represented by the following formula was prepared in the following manner.
<유도체 42의 화학식>       <Formula of derivative 42>
Figure PCTKR2009007995-appb-I000047
Figure PCTKR2009007995-appb-I000047
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실메탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(사이클로헥실메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 79%이었다. 이후 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(사이클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione)인 유도체 42를 수득하였다. 상기 수득한 유도체 42의 수율은 90%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.345(s, 1H), 7.748(s, 1H), 7.390(d, J=11.7Hz, 2H), 6.895(d, J=11.7Hz, 2H), 3.752(d, J=6.0Hz, 2H), 1.629-1.819(m, 6H). 1.152-1.301(m, 3H), 0.926-1.072(m, 2H)이었다.The intermediate product 4- (cyclohexylmethoxy) benzaldehyde was prepared in the same manner, except that cyclohexylmethanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. Obtained, wherein the yield of the intermediate product was 79%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. A derivative 42 was obtained, which is 4- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione). The yield of the obtained derivative 42 is 90%, 1 H NMR (300MHz, DMSO-d6) is δ 8.345 (s, 1H), 7.748 (s, 1H), 7.390 (d, J = 11.7 Hz, 2H), 6.895 (d, J = 11.7 Hz, 2H), 3.752 (d, J = 6.0 Hz, 2H), 1.629-1.819 (m, 6H). 1.152-1.301 (m, 3H) and 0.926-1.072 (m, 2H).
<실시예 43>      <Example 43>
본 발명에 따른 유도체 43의 제조Preparation of the derivative 43 according to the invention
하기 화학식으로 나타내는 유도체 43을 다음과 같은 방법으로 제조하였다.       Derivative 43 represented by the following formula was prepared in the following manner.
<유도체 43의 화학식>       <Formula of derivative 43>
Figure PCTKR2009007995-appb-I000048
Figure PCTKR2009007995-appb-I000048
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 1-메틸사이클로헥실메탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(1-메틸사이클로헥실메톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 80%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 43인 5-(4-((1-메틸사이클로헥실)메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-((1-Methylcyclohexyl)methoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 43의 수율은 91%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.487(s, 1H), 7.722(s, 1H), 7.545(d, J=8.7Hz, 2H), 7.108(d, J=8.7Hz, 2H), 3.754(s, 2H), 1.139-1.453(m, 7H), 1.310-1.337(m, 3H), 0.985(s, 3H)이었다.Except for using 1-methylcyclohexylmethanol instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2 using the same method as the intermediate product 4- (1-methylcyclo Hexylmethoxy) benzaldehyde was obtained wherein the yield of the intermediate product was 80%. Subsequently, the derivatives represented by the above formulas were subjected to the same method as described above, except that the obtained intermediate product was used instead of 4- (2-isopropoxyethoxy) benzaldehyde in the second step of the derivative manufacturing process of Example 1. Phosphorus 5- (4-((1-methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4-dione (5- (4-((1-Methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4 -dione) was obtained. The yield of the obtained derivative 43 is 91%, 1 H NMR (300MHz, DMSO-d6) is δ 12.487 (s, 1H), 7.722 (s, 1H), 7.545 (d, J = 8.7 Hz, 2H), 7.108 (d, J = 8.7 Hz, 2H), 3.754 (s, 2H), 1.139-1.453 (m, 7H), 1.310-1.337 (m, 3H), 0.985 (s, 3H).
<실시예 44>      <Example 44>
본 발명에 따른 유도체 44의 제조Preparation of the derivative 44 according to the invention
하기 화학식으로 나타내는 유도체 44를 다음과 같은 방법으로 제조하였다.      Derivative 44 represented by the following formula was prepared in the following manner.
<유도체 44의 화학식>       <Formula of derivative 44>
Figure PCTKR2009007995-appb-I000049
Figure PCTKR2009007995-appb-I000049
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 벤질알콜을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(벤질옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 92%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Benzyloxy)benzylidene)thiazolidine-2,4-dione)인 유도체 44를 수득하였다. 상기 수득한 유도체 44의 수율은 78%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.498(s, 1H), 7.736(s, 1H), 7.566(d, J=8.7Hz, 2H), 7.306-7.468(m, 5H), 7.18(d, J=8.7Hz, 2H), 5.176(s, 2H)이었다.The intermediate product 4- (benzyloxy) benzaldehyde was obtained by the same method except that benzyl alcohol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. The yield of this intermediate product was 92%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. A derivative 44 was obtained, which was (4- (benzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Benzyloxy) benzylidene) thiazolidine-2,4-dione). The yield of the obtained derivative 44 is 78%, 1 H NMR (300MHz, DMSO-d6) is δ 12.498 (s, 1H), 7.736 (s, 1H), 7.566 (d, J = 8.7 Hz, 2H), 7.306-7.468 (m, 5H), 7.18 (d, J = 8.7 Hz, 2H), 5.176 (s, 2H).
<실시예 45>      <Example 45>
본 발명에 따른 유도체 45의 제조Preparation of Derivative 45 According to the Invention
하기 화학식으로 나타내는 유도체 45를 다음과 같은 방법으로 제조하였다.      Derivative 45 represented by the following formula was prepared in the following manner.
<유도체 45의 화학식>       <Formula of derivative 45>
Figure PCTKR2009007995-appb-I000050
Figure PCTKR2009007995-appb-I000050
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥산올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(사이클로헥실옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 45인 5-(4-(사이클로헥실옥시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Cyclohexyloxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 45의 수율은 88%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.496(s, 1H), 7.724(s, 1H), 7.532(d, J=8.7Hz, 2H), 7.091(d, J=8.7Hz, 2H), 4.455(q, 1H), 1.865-2.073(m, 2H), 1.675-1.865(m, 2H), 1.446-1.547(m, 3H), 1.257-1.415 (m, 3H), 1.160-1.257(m, 1H)이었다.The intermediate product 4- (cyclohexyloxy) benzaldehyde was prepared in the same manner, except that cyclohexanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. Obtained, wherein the yield of the intermediate product was 94%. Thereafter, the derivative was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Cyclohexyloxy) benzylidene) thiazolidine-2,4-dione) was obtained. The yield of the obtained derivative 45 is 88%, 1 H NMR (300MHz, DMSO-d6) is δ 12.496 (s, 1H), 7.724 (s, 1H), 7.532 (d, J = 8.7 Hz, 2H), 7.091 (d, J = 8.7 Hz, 2H), 4.455 (q, 1H), 1.865-2.073 (m, 2H), 1.675-1.865 (m, 2H), 1.446-1.547 (m, 3H), 1.257-1.415 ( m, 3H) and 1.160-1.257 (m, 1H).
<실시예 46>      Example 46
본 발명에 따른 유도체 46의 제조Preparation of Derivative 46 According to the Invention
하기 화학식으로 나타내는 유도체 46을 다음과 같은 방법으로 제조하였다.      Derivative 46 represented by the following formula was prepared in the following manner.
<유도체 46의 화학식>      <Formula of derivative 46>
Figure PCTKR2009007995-appb-I000051
Figure PCTKR2009007995-appb-I000051
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 사이클로헥실에탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(사이클로헥실에틸옥시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 89%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 46인 5-(4-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 46의 수율은 81%이고, 1H NMR (300MHz, DMSO-d6)은 δ 8.195(s, 1H), 7.675(s, 1H), 7.473(d, J=14.7Hz, 2H), 6.895(d, J=14.7Hz, 2H), 4.036(t, J=11.7Hz, 2H), 1.565-1.727(m, 5H), 1.437-1.469(m, 1H), 1.041-1.223(m, 3H), 0.807-1.034(m, 2H)이었다.The intermediate product 4- (cyclohexylethyloxy) benzaldehyde was prepared in the same manner except that cyclohexylethanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2. Obtained, wherein the yield of the intermediate product was 89%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 46 is 81%, 1 H NMR (300MHz, DMSO-d6) is δ 8.195 (s, 1H), 7.675 (s, 1H), 7.473 (d, J = 14.7 Hz, 2H), 6.895 (d, J = 14.7 Hz, 2H), 4.036 (t, J = 11.7 Hz, 2H), 1.565-1.727 (m, 5H), 1.437-1.469 (m, 1H), 1.041-1.223 (m, 3H) , 0.807-1.034 (m, 2H).
<실시예 47>      <Example 47>
본 발명에 따른 유도체 47의 제조Preparation of Derivative 47 According to the Invention
하기 화학식으로 나타내는 유도체 47을 다음과 같은 방법으로 제조하였다. Derivative 47 represented by the following formula was prepared in the following manner.
<유도체 47의 화학식>       <Formula of derivative 47>
Figure PCTKR2009007995-appb-I000052
Figure PCTKR2009007995-appb-I000052
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 3-사이클로헥실-1-프로판올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(3-사이클로헥실프로폭시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 88%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 47인 5-(4-(3-사이클로헥실프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(3-Cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 47의 수율은 80%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.505(s, 1H), 7.730(s, 1H), 7.547(d, J=9.0Hz, 2H), 7.084(d, J=9.0Hz, 2H), 4.028(t, J=12.9Hz, 2H), 1.628-1.711(m, 7H), 1.143-1.300(m, 6H), 0.839-0.911(m, 2H)이었다.Except for using 3-cyclohexyl-1-propanol instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2, the intermediate product 4- (3- Cyclohexylpropoxy) benzaldehyde was obtained with a yield of 88% of the intermediate product. Thereafter, the derivative was obtained by the same method as in the second step of preparing the derivative of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (3-cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (3-Cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 47 is 80%, 1 H NMR (300MHz, DMSO-d6) is δ 12.505 (s, 1H), 7.730 (s, 1H), 7.547 (d, J = 9.0 Hz, 2H), 7.084 (d, J = 9.0 Hz, 2H), 4.028 (t, J = 12.9 Hz, 2H), 1.628-1.711 (m, 7H), 1.143-1.300 (m, 6H), 0.839-0.911 (m, 2H) It was.
<실시예 48>      <Example 48>
본 발명에 따른 유도체 48의 제조Preparation of Derivative 48 According to the Invention
하기 화학식으로 나타내는 유도체 48을 다음과 같은 방법으로 제조하였다.       Derivative 48 represented by the following formula was prepared in the following manner.
<유도체 48의 화학식>       <Formula of derivative 48>
Figure PCTKR2009007995-appb-I000053
Figure PCTKR2009007995-appb-I000053
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 4-사이클로헥실-1-부탄올을 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(4-사이클로헥실부톡시)벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 92%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 유도체 48인 5-(4-(4-사이클로헥실부톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(4-Cyclohexylbutoxy)benzylidene)thiazolidine-2,4-dione)을 수득하였다. 상기 수득한 유도체 48의 수율은 87%이고, 1H NMR (300MHz, DMSO-d6)은 δ 12.453(s, 1H), 7.407(s, 1H), 7.357(d, J=8.7Hz, 2H), 6.933(d, J=8.7Hz, 2H), 4.003(t, J=12.3Hz, 2H), 1.625-1.692(m, 6H), 1.37-1.1.398(m, 3H), 1.133-1.215(m, 4H), 0.815-0.956(m, 4H)이었다.Except that 4-cyclohexyl-1-butanol was used instead of 4- (2-hydroxyethyl) morpholine in the preparation of the derivative of Example 2, the intermediate product 4- (4- Cyclohexylbutoxy) benzaldehyde was obtained wherein the yield of the intermediate product was 92%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyethoxy) benzaldehyde was used. Phosphorus 5- (4- (4-cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (4-Cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione) was obtained. . The yield of the obtained derivative 48 is 87%, 1 H NMR (300MHz, DMSO-d6) is δ 12.453 (s, 1H), 7.407 (s, 1H), 7.357 (d, J = 8.7 Hz, 2H), 6.933 (d, J = 8.7 Hz, 2H), 4.003 (t, J = 12.3 Hz, 2H), 1.625-1.692 (m, 6H), 1.37-1.1.398 (m, 3H), 1.133-1.215 (m, 4H) and 0.815-0.956 (m, 4H).
<실시예 49>      <Example 49>
본 발명에 따른 유도체 49의 제조Preparation of Derivative 49 According to the Invention
하기 화학식으로 나타내는 유도체 49를 다음과 같은 방법으로 제조하였다.      Derivative 49 represented by the following formula was prepared in the following manner.
<유도체 49의 화학식>       <Formula of derivative 49>
Figure PCTKR2009007995-appb-I000054
Figure PCTKR2009007995-appb-I000054
상기 실시예 2의 유도체를 제조하는 과정에서 4-(2-히드록시에틸)모르폴린 대신 4-사이클로헥실에탄올을 사용하였고, 4-히드록시벤즈알데히드 대신 4-히드록시-3-니트로벤즈알데히드를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로헥실에톡시)-3-니트로벤즈알데히드를 수득하였으며, 이때 상기 중간체 생성물의 수율은 94%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 1의 유도체 제조 과정 중 제2 단계에서 4-(2-이소프로폭시에톡시)벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-사이클로헥실에톡시)-3-니트로벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-Cyclohexylethoxy)-3-nitrobenzylidene)thiazolidine-2,4-dione)인 유도체 49를 수득하였다. 상기 수득한 유도체 49의 수율은 85%이고, 1H NMR (300MHz, CDCl3)은 δ 9.931(s, 1H), 8.345(s, 1H), 8.081(d, J=10.2Hz, 1H), 7.267(d, J=10.2Hz, 1H), 4.190(t, J=12.9Hz, 2H), 1.839-1.934(m, 2H), 1.644-1.754(m, 4H), 1.335-1.408(m, 2H), 1.086-1.262(m, 3H), 0.864-0.970(m, 2H)이었다.In preparing the derivative of Example 2, 4-cyclohexylethanol was used instead of 4- (2-hydroxyethyl) morpholine, and 4-hydroxy-3-nitrobenzaldehyde was used instead of 4-hydroxybenzaldehyde. The same procedure was followed except for the intermediate product 4- (2-cyclohexylethoxy) -3-nitrobenzaldehyde, with a yield of 94%. Thereafter, the obtained intermediate product was subjected to the same method as in the second step of the derivative manufacturing process of Example 1, except that 4- (2-isopropoxyoxy) benzaldehyde was used. (4- (2-cyclohexylethoxy) -3-nitrobenzylidene) thiazolidine-2,4-dione (5- (4- (2-Cyclohexylethoxy) -3-nitrobenzylidene) thiazolidine-2,4- A derivative 49, dione) was obtained. The yield of the obtained derivative 49 is 85%, 1 H NMR (300MHz, CDCl 3 ) is δ 9.931 (s, 1H), 8.345 (s, 1H), 8.081 (d, J = 10.2 Hz, 1H), 7.267 (d, J = 10.2 Hz, 1H), 4.190 (t, J = 12.9 Hz, 2H), 1.839-1.934 (m, 2H), 1.644-1.754 (m, 4H), 1.335-1.408 (m, 2H), 1.086-1.262 (m, 3H) and 0.864-0.970 (m, 2H).
<실시예 50>      <Example 50>
본 발명에 따른 유도체 50의 제조Preparation of Derivative 50 According to the Invention
하기 화학식으로 나타내는 유도체 50을 다음과 같은 방법으로 제조하였다.      Derivative 50 represented by the following formula was prepared in the following manner.
<유도체 50의 화학식>       <Formula of derivative 50>
Figure PCTKR2009007995-appb-I000055
Figure PCTKR2009007995-appb-I000055
유도체 48 (1g, 2.7 mmol)을 함유하고 있는 메탄올-증류수 (9:1) 혼합용액 50ml에 Fe (1.49g, 27mmol) 및 FeSO4 (0.75g, 2.7mmol)를 혼합한 다음 환류하에서 7시간 동안 반응시켰다. 반응물을 여과하고 침전물은 뜨거운 메탄올을 이용하여 세척한 다음 여액과 혼합한다. 농축시킨 여액은 실리카겔이 충진된 컬럼크로마토그래피를 통해 정제하였으며, 이때 헥산 대 에틸아세테이트가 10:1이 되는 조건에서 용출시켜 상기 화학식으로 표시되는 유도체 50인 5-(3-아미노-4-(2-사이클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-Amino-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione) (0.85g, 수율 : 92%)을 수득하였다.50 ml of methanol-distilled water (9: 1) solution containing derivative 48 (1 g, 2.7 mmol) was mixed with Fe (1.49 g, 27 mmol) and FeSO 4 (0.75 g, 2.7 mmol) for 7 hours at reflux. Reacted. The reaction is filtered and the precipitate is washed with hot methanol and mixed with the filtrate. The concentrated filtrate was purified by silica gel-filled column chromatography. At this time, hexane to ethyl acetate was eluted under a condition of 10: 1 to obtain 5- (3-amino-4- (2), which is a derivative 50 represented by the above formula. -Cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-Amino-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione) (0.85 g, yield: 92 %) Was obtained.
<실시예 51><Example 51>
본 발명에 따른 유도체 51의 제조Preparation of Derivative 51 According to the Invention
하기 화학식으로 나타내는 유도체 51을 다음과 같은 방법으로 제조하였다.      Derivative 51 represented by the following formula was prepared in the following manner.
<유도체 51의 화학식>       <Formula of derivative 51>
Figure PCTKR2009007995-appb-I000056
Figure PCTKR2009007995-appb-I000056
시클로헥산메탄올(1g, 8.8mmol), 4-히드록시-3-메틸벤즈알데히드(1.20g, 8.8 mmol) 및 THF(20ml) 중의 트리페닐포스핀(2.54g, 9.7mmol)이 혼합된 용액에 디에틸 아조디카복실레이트(톨루엔 중의 40%, 9.7mmol)를 0℃에서 10분에 걸쳐 교반하면서 첨가하였다. 이후 상온에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드의 초기반응물질이 사라질 때까지 교반하였다. 상기 용액을 감압농축한 다음, 실리카 겔을 통한 크로마토그래피를 통해 정제하였으며, 이때 헥산 대 에틸 아세테이트가 10:1이 되는 조건에서 용출시켜 노란색 오일의 4-(2-시클로메톡시)-3-메틸벤즈알데히드(1.69g, 수율: 83%)를 수득하였다(제1 단계). 이후, 상기 제1 단계에서 수득한 4-(2-시클로메톡시)-3-메틸벤즈알데히드(1g, 4.3mmol)와 2,4-티아졸리딘디온(504mg, 4.3mmol)을 20ml의 톨루엔 용액으로 용해시켰고, 여기에 피페리딘(0.21ml, 2.15mmol) 및 아세트산(0.12ml, 2.15mmol)을 순차적으로 첨가한 후, 혼합액을 Dean-Stark 워터 트랩의 환류하에서 밤새도록 가열하였다. 이후 상기 혼합액을 냉각시킨 다음 여과시켰다. 이후 침전물은 헥산으로 세척한 후 건조시켜 노란색 고체의 상기 화학식으로 표시되는 유도체인 5-(4-(2-시클로핵실메톡시)-3-메틸벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylmethoxy)-3-methylbenzylidene)thiazolidine-2,4-dione)(1.10 g, 77.5% 수율)을 수득하였다(제2 단계). 상기 수득한 유도체 51의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7. 784(s,1H), 7.345(d, J = 8.4 Hz, 2H), 7.289 (s, 1H), 6.912(d, J = 8.4 Hz, 2H), 4.074 (d, J = 5.7 Hz, 2H), 2.302 (s, 3H), 1.706-1.894 (m, 6H), 1.257-1.380 (m, 3H), 1.070-1.225 (m, 2H)이었다.Diethyl to a solution mixed with cyclohexanemethanol (1 g, 8.8 mmol), 4-hydroxy-3-methylbenzaldehyde (1.20 g, 8.8 mmol) and triphenylphosphine (2.54 g, 9.7 mmol) in THF (20 ml) Azodicarboxylate (40% in toluene, 9.7 mmol) was added with stirring at 0 ° C. over 10 minutes. Thereafter, the reaction mixture was stirred until the initial reactant of cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde disappeared at room temperature. The solution was concentrated under reduced pressure and then purified by chromatography on silica gel, eluting with hexane to ethyl acetate at 10: 1 to give 4- (2-cyclomethoxy) -3-methyl as yellow oil. Benzaldehyde (1.69 g, yield: 83%) was obtained (first step). Thereafter, 4- (2-cyclomethoxy) -3-methylbenzaldehyde (1 g, 4.3 mmol) and 2,4-thiazolidinedione (504 mg, 4.3 mmol) obtained in the first step were added to 20 ml of toluene solution. After dissolving, piperidine (0.21 ml, 2.15 mmol) and acetic acid (0.12 ml, 2.15 mmol) were added sequentially, and the mixture was heated overnight under reflux of the Dean-Stark water trap. The mixture was then cooled and filtered. The precipitate is then washed with hexane and dried to give 5- (4- (2-cyclonucleomethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione which is a derivative represented by the above formula as a yellow solid. 5- (4- (2-cyclohexylmethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione) (1.10 g, 77.5% yield) was obtained (second step). The compound of Derivative 51 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7. 784 (s, 1H), 7.345 (d, J = 8.4 Hz, 2H), 7.289 (s, 1H), 6.912 (d, J = 8.4 Hz, 2H), 4.074 (d, J = 5.7 Hz, 2H), 2.302 (s, 3H), 1.706-1.894 (m, 6H), 1.257-1.380 (m, 3H), 1.070-1.225 (m, 2H).
<실시예 52><Example 52>
본 발명에 따른 유도체 52의 제조Preparation of Derivative 52 According to the Invention
하기 화학식으로 나타내는 유도체 52를 다음과 같은 방법으로 제조하였다.      Derivative 52 represented by the following formula was prepared in the following manner.
<유도체 52의 화학식>       <Formula of derivative 52>
Figure PCTKR2009007995-appb-I000057
Figure PCTKR2009007995-appb-I000057
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 3-시클로헥실-1-프로판올(1g, 7.0mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(0.95g, 7.0mmol)를 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로헥실프로폭시)-3-메틸벤즈알데히드 1.46g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 80%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-사이클로헥실프로폭시)-3-메틸벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylpropoxy)-3-methylbenzylidene)thiazolidine-2,4-dione) 1.23g을 수득하였고, 수득율은 89.1% 였다. 상기 수득한 유도체 52의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.793(s,1H),7.349(d, J = 8.4 Hz, 2H), 7.312 (s, 1H), 6.898 (d, J = 8.4 Hz, 2H), 4.029 (t, J = 13.2 Hz, 2H), 1.650-2.041 (m, 8H), 1.089-1.397 (m, 4H), 0.860-0.968 (m, 3H)이었다. In the preparation of the derivative of Example 51, 3-cyclohexyl-1-propanol (1 g, 7.0 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. The same procedure was used to obtain 1.46 g of the intermediate product 4- (2-cyclohexylpropoxy) -3-methylbenzaldehyde, except that oxybenzaldehyde (0.95 g, 7.0 mmol) was used, wherein the yield of the intermediate product was obtained. Was 80%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4- (2-cyclohexylpropoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylpropoxy) -3-methylbenzylidene) thiazolidine-2,4 -dione) was obtained. The yield was 89.1%. The compound of Derivative 52 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ7.793 (s, 1H), 7.349 (d, J = 8.4 Hz, 2H), 7.312 (s, 1H), 6.898 ( d, J = 8.4 Hz, 2H), 4.029 (t, J = 13.2 Hz, 2H), 1.650-2.041 (m, 8H), 1.089-1.397 (m, 4H), 0.860-0.968 (m, 3H).
<실시예 53><Example 53>
본 발명에 따른 유도체 53의 제조Preparation of Derivative 53 According to the Invention
하기 화학식으로 나타내는 유도체 53을 다음과 같은 방법으로 제조하였다.      Derivative 53 represented by the following formula was prepared in the following manner.
<유도체 53의 화학식>       <Formula of derivative 53>
Figure PCTKR2009007995-appb-I000058
Figure PCTKR2009007995-appb-I000058
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-시클로헥실-1-부판올(1g, 6.4mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드를 0.87g, 6.4mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-사이클로헥실부톡시)-3-메틸벤즈알데히드를 1.43g 수득하였으며, 이때 상기 중간체 생성물의 수율은 81%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-사이클로헥실부톡시)-3-메틸벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylbutoxy)-3-methylbenzylidene)thiazolidine-2,4-dione) 1.19g을 수득하였고, 수득율은 87.5% 였다. 상기 수득한 유도체 53의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.787(s,1H),7.421(d, J = 8.7 Hz, 2H), 7.291 (s, 1H), 6.903(d, J = 8.7Hz, 2H), 4.045 (t, J = 12.9 Hz, 2H), 1.806-1.852 (m, 2H), 1.694-1.779 (m, 5H), 1.438-1.510 (m, 2H), 1.174-1.266 (m, 6H), 0.857-0.890 (m, 2H)이었다.In preparing the derivative of Example 51, 4-cyclohexyl-1-butanol (1 g, 6.4 mmol) was used instead of cyclohexane methanol, and 0.87 g of 4-hydroxy-3-methylbenzaldehyde was used. Using the same method, except that the amount was used, 1.43 g of the intermediate product 4- (2-cyclohexylbutoxy) -3-methylbenzaldehyde was obtained, and the yield of the intermediate product was 81%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4- (2-cyclohexylbutoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylbutoxy) -3-methylbenzylidene) thiazolidine-2,4 -dione) was obtained. The yield was 87.5%. The compound of Derivative 53 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ7.787 (s, 1H), 7.421 (d, J = 8.7 Hz, 2H), 7.291 (s, 1H), 6.903 ( d, J = 8.7 Hz, 2H), 4.045 (t, J = 12.9 Hz, 2H), 1.806-1.852 (m, 2H), 1.694-1.779 (m, 5H), 1.438-1.510 (m, 2H), 1.174 -1.266 (m, 6H), 0.857-0.890 (m, 2H).
<실시예 54><Example 54>
본 발명에 따른 유도체 54의 제조Preparation of Derivative 54 According to the Invention
하기 화학식으로 나타내는 유도체 54를 다음과 같은 방법으로 제조하였다.      Derivative 54 represented by the following formula was prepared in the following manner.
<유도체 54의 화학식>       <Formula of derivative 54>
Figure PCTKR2009007995-appb-I000059
Figure PCTKR2009007995-appb-I000059
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드 대신 페놀(1g, 10.6mmol) 및 4-히드록시벤즈알데히드(1.29g, 10.6mmol)을 사용하고, 트리페닐포스피린을 3.06g, 11.66mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-페녹시벤즈알데히드를 1.2g 수득하였으며, 이때 상기 중간체 생성물의 수율은 57%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-페녹시벤질리덴)-1,3-티아졸리딘-2,4-디온(5-(4-phenoxybenzylidene)-1,3-thiazolidine-2,4-dione)을 1.02g 수득하였고, 수율은 72.0%이었다. 상기 수득한 유도체 53의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ8.302(s,1H),7.536-7.639(m,5H),7.349(d, J = 8.4 Hz, 2H), 6.903(d, J = 8.4 Hz, 2H)이었다.In the preparation of the derivative of Example 51, phenol (1 g, 10.6 mmol) and 4-hydroxybenzaldehyde (1.29 g, 10.6 mmol) were used instead of cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde. 1.2 g of the intermediate product, 4-phenoxybenzaldehyde, was obtained using the same method except that phenylphosphoryne was used in an amount of 3.06 g and 11.66 mmol, wherein the yield of the intermediate product was 57%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 1.02 g of 5- (4-phenoxybenzylidene) -1,3-thiazolidine-2,4-dione (5- (4-phenoxybenzylidene) -1,3-thiazolidine-2,4-dione) was obtained. The yield was 72.0%. The compound of Derivative 53 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ8.302 (s, 1H), 7.536-7.639 (m, 5H), 7.349 (d, J = 8.4 Hz, 2H), 6.903 (d, J = 8.4 Hz, 2H).
<실시예 55><Example 55>
본 발명에 따른 유도체 55의 제조Preparation of Derivative 55 According to the Invention
하기 화학식으로 나타내는 유도체 55를 다음과 같은 방법으로 제조하였다.      Derivative 55 represented by the following formula was prepared in the following manner.
<유도체 55의 화학식>       <Formula of derivative 55>
Figure PCTKR2009007995-appb-I000060
Figure PCTKR2009007995-appb-I000060
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드 대신 2-페닐에탄올(1g, 8.2.mmol) 및 4-히드록시벤즈알데히드(1.0g, 8.2mmol)을 사용하고, 트리페닐포스피린을 2.37g, 9.02mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-페닐에톡시)벤즈알데히드를 1.5g 수득하였으며, 이때 상기 중간체 생성물의 수율은 79%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-(2-페닐에톡시)벤질리덴]-1,3-티아졸리딘-2,4-디온(5-[4-(2-phenylethoxy)benzylidene]-1,3-thiazolidine-2,4-dione) 을 0.94g 수득하였고, 수율은 62.7%였다. 상기 수득한 유도체 55의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.806(s,1H),7.466(d, J = 8.7 Hz, 2H), 7.262-7.369 (m, 5H), 7.196 (d, J = 8.7Hz, 2H), 4.261 (t, J = 14.1 Hz, 2H), 3.153 (t, J = 14.1 Hz, 2H)이었다.In preparing the derivative of Example 51, 2-phenylethanol (1 g, 8.2. Mmol) and 4-hydroxybenzaldehyde (1.0 g, 8.2 mmol) were substituted for cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde. 1.5 g of the intermediate product 4- (2-phenylethoxy) benzaldehyde was obtained using the same method, except that triphenylphosphine was used in an amount of 2.37 g and 9.02 mmol. The yield was 79%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- [4- (2-phenylethoxy) benzylidene] -1,3-thiazolidine-2,4-dione (5- [4- (2-phenylethoxy) benzylidene] -1,3-thiazolidine-2 , 4-dione) was obtained and the yield was 62.7%. The obtained compound of Derivative 55 is 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.806 (s, 1 H), 7.466 (d, J = 8.7 Hz, 2H), 7.262-7.369 (m, 5H), 7.196 (d, J = 8.7 Hz, 2H), 4.261 (t, J = 14.1 Hz, 2H), 3.153 (t, J = 14.1 Hz, 2H).
<실시예 56><Example 56>
본 발명에 따른 유도체 56의 제조Preparation of the derivative 56 according to the invention
하기 화학식으로 나타내는 유도체 56을 다음과 같은 방법으로 제조하였다.      Derivative 56 represented by the following formula was prepared in the following manner.
<유도체 56의 화학식>      <Formula of derivative 56>
Figure PCTKR2009007995-appb-I000061
Figure PCTKR2009007995-appb-I000061
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드 대신 3-페닐-1-프로판올(1g, 7.3mmol) 및 4-히드록시벤즈알데히드(0.89g, 7.3mmol)을 사용하고, 트리페닐포스피린을 2.11g, 8.03mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(3-페닐프로폭시)벤즈알데히드를 1.52g 수득하였으며, 이때 상기 중간체 생성물의 수율은 86.4%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-(2-페닐프로폭시)벤질리덴]-1,3-티아졸리딘-2,4-디온(5-[4-(2-phenylpropoxy)benzylidene]-1,3-thiazolidine-2,4-dione)을 1.12g 수득하였으며, 수득율을 80.1%이었다. 상기 수득한 유도체 56의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.820(s,1H),7.465(d, J = 8.7 Hz, 2H), 7.201-7.329 (m, 5H), 6.993 (d, J = 8.7 Hz, 2H), 4.020 (t, J = 12.3 Hz, 2H), 2.851 (t, J = 15.0 Hz, 2H), 2.094-2.187 (m, 2H)이었다.In the preparation of the derivative of Example 51, 3-phenyl-1-propanol (1 g, 7.3 mmol) and 4-hydroxybenzaldehyde (0.89 g, 7.3 mmol) instead of cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde ) And 1.52 g of the intermediate product 4- (3-phenylpropoxy) benzaldehyde was obtained using the same method except that triphenylphosphine was used in an amount of 2.11 g and 8.03 mmol, wherein the intermediate The yield of the product was 86.4%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- [4- (2-phenylpropoxy) benzylidene] -1,3-thiazolidine-2,4-dione (5- [4- (2-phenylpropoxy) benzylidene] -1,3-thiazolidine-2 , 4-dione) was obtained, and the yield was 80.1%. The compound of Derivative 56 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.820 (s, 1H), 7.465 (d, J = 8.7 Hz, 2H), 7.201-7.329 (m, 5H), 6.993 (d, J = 8.7 Hz, 2H), 4.020 (t, J = 12.3 Hz, 2H), 2.851 (t, J = 15.0 Hz, 2H), 2.094-2.187 (m, 2H).
<실시예 57><Example 57>
본 발명에 따른 유도체 57의 제조Preparation of the derivative 57 according to the invention
하기 화학식으로 나타내는 유도체 57을 다음과 같은 방법으로 제조하였다.      Derivative 57 represented by the following formula was prepared in the following manner.
<유도체 57의 화학식>      <Formula of derivative 57>
Figure PCTKR2009007995-appb-I000062
Figure PCTKR2009007995-appb-I000062
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 및 4-히드록시-3-메틸벤즈알데히드 대신 4-페닐-1-부탄올(1g, 6.7mmol) 및 4-히드록시벤즈알데히드(0.82g, 6.7mmol)을 사용하고, 트리페닐포스피린을 1.93g, 7.37mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(3-페닐부톡시)벤즈알데히드를 1.42g 수득하였으며, 이때 상기 중간체 생성물의 수율은 84%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-(2-페닐부톡시)벤질리덴]-1,3-티아졸리딘-2,4-디온(5-[4-(2-phenylbutoxy)benzylidene]-1,3-thiazolidine-2,4-dione)을 1.15g 수득하였으며, 수득율을 85%이었다. 상기 수득한 유도체 57의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.816(s,1H),7.468(d, J = 8.7 Hz, 2H), 7.174-7.323(m, 5H), 6.903 (d, J = 8.7 Hz, 2H), 4.048 (t, J = 11.7 Hz, 2H), 2.724 (t, J = 13.8 Hz, 2H), 1.786-1.876 (m, 4H)이었다.4-phenyl-1-butanol (1 g, 6.7 mmol) and 4-hydroxybenzaldehyde (0.82 g, 6.7 mmol) instead of cyclohexanemethanol and 4-hydroxy-3-methylbenzaldehyde in the preparation of the derivative of Example 51 ) And 1.42 g of the intermediate product 4- (3-phenylbutoxy) benzaldehyde were obtained in the same manner except that triphenylphosphine was used in an amount of 1.93 g and 7.37 mmol, wherein the intermediate The yield of the product was 84%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- [4- (2-phenylbutoxy) benzylidene] -1,3-thiazolidine-2,4-dione (5- [4- (2-phenylbutoxy) benzylidene] -1,3-thiazolidine-2 , 4-dione) was obtained, and the yield was 85%. The compound of Derivative 57 obtained was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.816 (s, 1H), 7.468 (d, J = 8.7 Hz, 2H), 7.174-7.323 (m, 5H), 6.903 (d, J = 8.7 Hz, 2H), 4.048 (t, J = 11.7 Hz, 2H), 2.724 (t, J = 13.8 Hz, 2H), 1.786-1.876 (m, 4H).
<실시예 58><Example 58>
본 발명에 따른 유도체 58의 제조Preparation of the derivative 58 according to the invention
하기 화학식으로 나타내는 유도체 58을 다음과 같은 방법으로 제조하였다.      Derivative 58 represented by the following formula was prepared in the following manner.
<유도체 58의 화학식>      <Formula of derivative 58>
Figure PCTKR2009007995-appb-I000063
Figure PCTKR2009007995-appb-I000063
수소화나트륨(24.14mg, 1.0mmol, 60% 분산 오일)을 DMF 20ml에 5-4-(2-시클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(200mg, 0.60mmol)이 존재하는 용액에 첨가한 다음, 상온의 온도에서 질소 조건하에 교반하였다. 이후 혼합물을 10 분 동안 더 교반한 후, 상기 혼합액에 DMF 5ml에 녹아있는 2-요오드에탄올(123.81mg, 0.72 mmol)을 천천히 첨가하였고, 60℃에서 48시간 동안 교반하였다. 이후 상기 반응 혼합물을 에틸 아세테이트로 추출하고 물로 세척하였다. 유기층은 무수화 황 마그네슘을 사용하여 건조시키고 여과 및 증발시켰다. 이후 잔여물은 실리카 겔 크로마토그래피를 사용하여 정제하였으며, 이대 용출은 헥산 및 에틸 아세테이트가 10:1로 혼합된 용매를 사용하였으며, 그 결과 180mg의 상기 화학식으로 표시되는 유도체 58 화합물인 5-(4-(2-시클로헥실에톡시)벤질리덴]-3-(히드록시에틸)-1,3-티아졸리디온-2,4-디온(5-[4-(2-cyclohexylethoxy)benzylidene]-3-(hydroxyethyl)-1,3-thiazolidine-2,4-dione)(79% 수득율)을 수득하였으며, 상기 유도체 58의 화합물은 1H NMR (300 MHz, CDCl3) δ7.878(s, 1H), 7.485 (d, J = 14.4 Hz, 2H), 7.007 (d, J = 14.4 Hz, 2H), 4.078 (t, J = 13.2 Hz, 2H), 4.001 (t, J = 10.2 Hz, 2H), 3.891 (t, J = 10.2 Hz, 2H), 2.049 (m, 1H), 1.670-1.782 (m, 7H), 1.471-1.529 (m, 1H), 1.178-1.284 (m, 3H), 0.956-1.034 (m, 2H)이었다.Sodium hydride (24.14 mg, 1.0 mmol, 60% dispersion oil) is present in 20 ml of DMF with 5-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (200 mg, 0.60 mmol) The solution was added to the resulting solution, followed by stirring at room temperature under nitrogen. After further stirring the mixture for 10 minutes, 2-iodineethanol (123.81 mg, 0.72 mmol) dissolved in 5 ml of DMF was slowly added to the mixture, and the mixture was stirred at 60 ° C. for 48 hours. The reaction mixture was then extracted with ethyl acetate and washed with water. The organic layer was dried using magnesium sulfate anhydride, filtered and evaporated. The residue was then purified using silica gel chromatography. This elution was carried out using a solvent in which hexane and ethyl acetate were mixed at 10: 1, resulting in 180 mg of the derivative 58 compound represented by the above formula (5- (4). -(2-cyclohexylethoxy) benzylidene] -3- (hydroxyethyl) -1,3-thiazolidione-2,4-dione (5- [4- (2-cyclohexylethoxy) benzylidene] -3- (hydroxyethyl) -1,3-thiazolidine-2,4-dione) (79% yield) was obtained, and the compound of the derivative 58 was 1 H NMR (300 MHz, CDCl 3 ) δ 7.878 (s, 1H), 7.485 (d, J = 14.4 Hz, 2H), 7.007 (d, J = 14.4 Hz, 2H), 4.078 (t, J = 13.2 Hz, 2H), 4.001 (t, J = 10.2 Hz, 2H), 3.891 ( t, J = 10.2 Hz, 2H), 2.049 (m, 1H), 1.670-1.782 (m, 7H), 1.471-1.529 (m, 1H), 1.178-1.284 (m, 3H), 0.956-1.034 (m, 2H).
<실시예 59><Example 59>
본 발명에 따른 유도체 59의 제조Preparation of the derivative 59 according to the invention
하기 화학식으로 나타내는 유도체 59를 다음과 같은 방법으로 제조하였다.      Derivative 59 represented by the following formula was prepared in the following manner.
<유도체 59의 화학식>      <Formula of derivative 59>
Figure PCTKR2009007995-appb-I000064
Figure PCTKR2009007995-appb-I000064
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올을 1g, 7.8mmol 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-에톡시-4-히드록시알데히드(1.30g, 7.8mmol)를 사용하였으며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-시클로헥실에톡시)-3-에톡시벤즈알데히드를 1.85g 수득하였으며, 이때 상기 중간체 생성물의 수율은 85.7%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-시클로헥실에톡시)-3-에톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylethoxy)-3-ethoxybenzylidene)thiazolidine-2,4-dion)(1.12 g, 83.0% 수율)을 수득하였으며, 상기 유도체 59의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ12.582 (s, 1H), 7.786 (s, 1H), 7.116 (d, J = 10.8 Hz, 1H), 6.959 (d, J=10.8 Hz, 1H), 7.000 (s, 1H), 4.089 (m, 4H), 1.653-1.795 (m, 7H), 1.459-1.577 (m, 4H), 1.146-1.282 (m, 3H), 0.941-1.05 (m, 2H)이었다.In preparing the derivative of Example 51, 1 g, 7.8 mmol of cyclohexaneethanol was used instead of cyclohexane methanol, and 3-ethoxy-4-hydroxy aldehyde (1.30 g, instead of 4-hydroxy-3-methylbenzaldehyde) was used. 7.8 mmol), and the intermediate product 4- (2-cyclohexylethoxy) -3-ethoxybenzaldehyde was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.85 g were obtained, wherein the yield of the intermediate product was 85.7%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4- (2-cyclohexylethoxy) -3-ethoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylethoxy) -3-ethoxybenzylidene) thiazolidine-2, 4-dion) (1.12 g, 83.0% yield) was obtained, and the compound of the derivative 59 was prepared by 1 H NMR (300 MHz, DMSO- d 6 ) δ12.582 (s, 1H), 7.786 (s, 1H), 7.116 (d, J = 10.8 Hz, 1H), 6.959 (d, J = 10.8 Hz, 1H), 7.000 (s, 1H), 4.089 (m, 4H), 1.653-1.795 (m, 7H), 1.459-1.577 (m, 4H), 1.146-1.282 (m, 3H), and 0.941-1.05 (m, 2H).
<실시예 60><Example 60>
본 발명에 따른 유도체 60의 제조Preparation of Derivative 60 According to the Invention
하기 화학식으로 나타내는 유도체 60을 다음과 같은 방법으로 제조하였다.      Derivative 60 represented by the following formula was prepared in the following manner.
<유도체 60의 화학식>      <Formula of derivative 60>
Figure PCTKR2009007995-appb-I000065
Figure PCTKR2009007995-appb-I000065
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올 1g, 7.8mmol 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-메톡시-4-히드록시벤즈알데히드(1.19g, 7.8mmol)를 사용하였으며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-시클로헥실에톡시)-2-메톡시벤즈알데히드를 1.78g 수득하였으며, 이때 상기 중간체 생성물의 수율은 87.3%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-시클로헥실에톡시)-2-메톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylethoxy)-2-methoxybenzylidene)thiazolidine-2,4-dione) (1.15 g, 83.9% 수득율)을 수득하였으며, 상기 유도체 60 화합물은 1H NMR (300 MHz, DMSO-d 6)δ12.446 (s, 1H), 7.915 (s, 1H), 7.907 (d, J = 8.4 Hz, 1H), 6.709 (d, J=8.4 Hz, 1H), 6.667 (s, 1H), 4.102 (t, J = 5.1 Hz, 2H), 3.878 (s, 3H), 1.587-1.750 (m, 7H), 1.451-1.586 (m, 1H), 1.104-1.271 (m, 3H), 0.884-0.994 (m, 2H)이었다. In preparing the derivative of Example 51, instead of cyclohexanemethanol, 1 g and 7.8 mmol of cyclohexaneethanol were used, and 2-methoxy-4-hydroxybenzaldehyde (1.19 g, 7.8 instead of 4-hydroxy-3-methylbenzaldehyde) was used. mmol), and the intermediate product 4- (2-cyclohexylethoxy) -2-methoxybenzaldehyde was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. g was obtained, wherein the yield of the intermediate product was 87.3%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4- (2-cyclohexylethoxy) -2-methoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylethoxy) -2-methoxybenzylidene) thiazolidine-2, 4-dione) (1.15 g, 83.9% yield) was obtained and the derivative 60 compound was subjected to 1 H NMR (300 MHz, DMSO- d 6 ) δ12.446 (s, 1H), 7.915 (s, 1H), 7.907 (d, J = 8.4 Hz, 1H), 6.709 (d, J = 8.4 Hz, 1H), 6.667 (s, 1H), 4.102 (t, J = 5.1 Hz, 2H), 3.878 (s, 3H), 1.587 -1.750 (m, 7H), 1.451-1.586 (m, 1H), 1.104-1.271 (m, 3H), 0.884-0.994 (m, 2H).
<실시예 61><Example 61>
본 발명에 따른 유도체 61의 제조Preparation of Derivative 61 According to the Invention
하기 화학식으로 나타내는 유도체 61을 다음과 같은 방법으로 제조하였다.      Derivative 61 represented by the following formula was prepared in the following manner.
<유도체 61의 화학식>      <Formula of derivative 61>
Figure PCTKR2009007995-appb-I000066
Figure PCTKR2009007995-appb-I000066
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-(시클로헥실옥시)에탄올 1g, 6.9mmol을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시벤즈알데히드(0.84g, 6.9mmol)를 사용하였으며, 트리페닐포스피린을 1.99g, 7.59mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-(시클로헥실옥시)에톡시)벤즈알데히드를 1.46g 수득하였으며, 이때 상기 중간체 생성물의 수율은 84.9%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-(시클로헥실옥시)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-(Cyclohexyloxy)ethoxy)benzylidene)thiazolidine-2,4-dione)(1.14 g, 82.0% 수율)을 수득하였고, 상기 유도체 61 화합물은 1H NMR (300 MHz, DMSO-d 6)δ8.645 (s, 1H), 7.733 (s, 1H), 7.437 (d, J = 14.7 Hz, 2H), 7.020 (d, J = 14.7 Hz, 2H), 4.197 (t, J = 9.9 Hz, 2H), 3.302 (t, J = 9.9 Hz, 2H), 3.321-3.397 (m, 1H), 1.956-2.179 (m, 2H), 1.754-1.770 (m, 2H), 1.549-1.592 (m, 1H), 1.218-1.389 (m, 5H)이었다.In preparing the derivative of Example 51, 1 g and 6.9 mmol of 2- (cyclohexyloxy) ethanol instead of cyclohexanemethanol were used, and 4-hydroxybenzaldehyde (0.84 g instead of 4-hydroxy-3-methylbenzaldehyde) was used. , 6.9 mmol), and the intermediate product 4- (2- (cyclohexyloxy) ethoxy) benzaldehyde was prepared in the same manner except that triphenylphosphine was used in an amount of 1.99 g and 7.59 mmol. 1.46 g were obtained, wherein the yield of the intermediate product was 84.9%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4- (2- (cyclohexyloxy) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2- (Cyclohexyloxy) ethoxy) benzylidene) thiazolidine-2,4 -dione) (1.14 g, 82.0% yield), and the derivative 61 compound was subjected to 1 H NMR (300 MHz, DMSO- d 6 ) δ8.645 (s, 1H), 7.733 (s, 1H), 7.437 ( d, J = 14.7 Hz, 2H), 7.020 (d, J = 14.7 Hz, 2H), 4.197 (t, J = 9.9 Hz, 2H), 3.302 (t, J = 9.9 Hz, 2H), 3.321-3.397 ( m, 1H), 1.956-2.179 (m, 2H), 1.754-1.770 (m, 2H), 1.549-1.592 (m, 1H), 1.218-1.389 (m, 5H).
<실시예 62><Example 62>
본 발명에 따른 유도체 62의 제조Preparation of Derivative 62 According to the Invention
하기 화학식으로 나타내는 유도체 62를 다음과 같은 방법으로 제조하였다.      Derivative 62 represented by the following formula was prepared in the following manner.
<유도체 62의 화학식>      <Formula of derivative 62>
Figure PCTKR2009007995-appb-I000067
Figure PCTKR2009007995-appb-I000067
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-히드록시메틸-1,4-벤조디옥산 1g, 6.0mmol을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시벤즈알데히드(0.73g, 6.0mmol)를 사용하였으며, 트리페닐포스피린을 1.73g, 6.6mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-((2,3-디히드로벤조[b][1,4]디옥신-2-일)메톡시)벤즈알데히드를 1.34g 수득하였으며, 이때 상기 중간체 생성물의 수율은 82.7%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-((2,3-디히드로벤조[b][1,4]디옥신-2-일)메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methoxy) benzylidene)thiazolidine-2,4-dione)(1.12 g, 82.4% 수율)을 수득하였으며, 상기 유도체 62의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ12.513 (s, 1H), 7.733 (s, 1H), 7.576 (d, J=8.7 Hz, 2H), 7.167 (d, J=8.7 Hz, 2H), 6.817-6.922 (m, 4H), 4.458-4.578 (m, 1H), 4.409-4.455 (m, 1H), 4.263-4.409 (m, 2H), 4.111-4.173 (m, 1H)이었다.In preparing the derivative of Example 51, 2-hydroxymethyl-1,4-benzodioxane 1g, 6.0mmol was used instead of cyclohexanemethanol, and 4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Benzaldehyde (0.73 g, 6.0 mmol) was used, and the intermediate product 4-((2,3-dihydrobenzo [was used in the same manner except that triphenylphosphine was used in an amount of 1.73 g and 6.6 mmol. b] 1.34 g of [1,4] dioxin-2-yl) methoxy) benzaldehyde were obtained, with a yield of 82.7% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4-((2,3-dihydrobenzo [b] [1,4] dioxin-2-yl) methoxy) benzylidene) thiazolidine-2,4-dione (5- (4- ((2,3-Dihydrobenzo [b] [1,4] dioxin-2-yl) methoxy) benzylidene) thiazolidine-2,4-dione) (1.12 g, 82.4% yield) was obtained, and the compound of the derivative 62 was obtained. Silver 1 H NMR (300 MHz, DMSO- d 6 ) δ12.513 (s, 1H), 7.733 (s, 1H), 7.576 (d, J = 8.7 Hz, 2H), 7.167 (d, J = 8.7 Hz, 2H), 6.817-6.922 (m, 4H), 4.458-4.578 (m, 1H), 4.409-4.455 (m, 1H), 4.263-4.409 (m, 2H), 4.111-4.173 (m, 1H).
<실시예 63><Example 63>
본 발명에 따른 유도체 63의 제조Preparation of Derivative 63 According to the Invention
하기 화학식으로 나타내는 유도체 63을 다음과 같은 방법으로 제조하였다.      Derivative 63 represented by the following formula was prepared in the following manner.
<유도체 63의 화학식>      <Formula of derivative 63>
Figure PCTKR2009007995-appb-I000068
Figure PCTKR2009007995-appb-I000068
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올을 1g, 8.8mmol 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.38g, 8.8mmol)를 사용하며, 트리페닐포스피린을 2.54g, 9.68mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(시클로헥실메톡시)벤즈알데히드를 1.89g 수득하였으며, 이때 상기 중간체 생성물의 수율은 85.5%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(시클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione)(1.06 g, 76.3% 수율)을 수득하였으며, 상기 유도체 63 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.721(s,1H),7.514 (d, J = 9.3 Hz, 1H), 7.138-7.327(m, 1H), 7.142 (d, J=9.3Hz,1H),3.862(d,J=6.0Hz,2H), 1.7.3-1.933 (m, 6H), 1.088-1.579 (m, 5H)이었다.In preparing the derivative of Example 51, 1 g, 8.8 mmol of cyclohexanemethanol was used, and 2-chloro-3-hydroxybenzaldehyde (1.38 g, 8.8 mmol) was used instead of 4-hydroxy-3-methylbenzaldehyde. Using the same method, except that triphenylphosphine was used in an amount of 2.54 g and 9.68 mmol, 1.89 g of an intermediate product, 2-chloro-3- (cyclohexylmethoxy) benzaldehyde, was obtained. The yield of the product was 85.5%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione) (1.06 g, 76.3% yield), and the derivative 63 compound was prepared by 1 H NMR (300 MHz, DMSO- d 6 ) δ7.721 (s, 1H), 7.514 (d, J = 9.3 Hz, 1H), 7.138-7.327 (m, 1H), 7.142 (d, J = 9.3 Hz, 1H), 3.862 (d, J = 6.0 Hz, 2H), 1.7.3-1.933 (m, 6H), 1.088-1.579 (m, 5H).
<실시예 64><Example 64>
본 발명에 따른 유도체 64의 제조Preparation of the derivative 64 according to the invention
하기 화학식으로 나타내는 유도체 64를 다음과 같은 방법으로 제조하였다.      Derivative 64 represented by the following formula was prepared in the following manner.
<유도체 64의 화학식>      <Formula of derivative 64>
Figure PCTKR2009007995-appb-I000069
Figure PCTKR2009007995-appb-I000069
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 3-시클로헥실-1-프로판올(1g, 7.0mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(855mg, 7.0mmol)를 사용하며, 트리페닐포스피린을 2.02g, 7.7mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(시클로헥실프로폭시)벤즈알데히드를 1.65g 수득하였으며, 이때 상기 중간체 생성물의 수율은 83.8%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(시클로헥실프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)(1.00 g, 74.1% 수율)을 수득하였으며, 상기 유도체 64 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.943(s,1H),7.521 (d, J = 9.3 Hz, 1H), 7.261-7.333 (m, 1H), 7.152 (d, J=9.3Hz,1H),4.045(t,J=13.2Hz,2H), 1.829-1.925 (m, 2H), 1.578-1.731 (m, 5H), 1.091-1.426 (m, 6H), 0.859-0.883 (m, 2H)이었다.3-cyclohexyl-1-propanol (1 g, 7.0 mmol) was used instead of cyclohexanemethanol in the process of preparing the derivative of Example 51, and 2-chloro-3-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Roxybenzaldehyde (855 mg, 7.0 mmol) was used, and the intermediate product 2-chloro-3- (cyclohexylpropoxy) was obtained using the same method except that triphenylphosphine was used in an amount of 2.02 g, 7.7 mmol. 1.65 g of benzaldehyde was obtained, wherein the yield of the intermediate product was 83.8%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione) (1.00 g, 74.1% yield), wherein the derivative 64 compound was prepared by 1 H NMR (300 MHz, DMSO- d 6 ) δ7.943 (s, 1H), 7.521 (d, J = 9.3 Hz, 1H), 7.261-7.333 (m, 1H), 7.152 (d, J = 9.3 Hz, 1H), 4.045 (t, J = 13.2 Hz, 2H), 1.829-1.925 (m, 2H), 1.578-1.731 (m, 5H) , 1.091-1.426 (m, 6H) and 0.859-0.883 (m, 2H).
<실시예 65><Example 65>
본 발명에 따른 유도체 65의 제조Preparation of the derivative 65 according to the invention
하기 화학식으로 나타내는 유도체 65를 다음과 같은 방법으로 제조하였다.      Derivative 65 represented by the following formula was prepared in the following manner.
<유도체 65의 화학식>      <Formula of derivative 65>
Figure PCTKR2009007995-appb-I000070
Figure PCTKR2009007995-appb-I000070
수소화 나트륨(342.2mg, 8.58mmol, 60%의 분산 오일)에 건조된 디메틸포름아마이드(30ml)에 존재하는 4-메틸-1-시클로헥산메탄올(1g, 7.8mmol)을 첨가한 후 상온에서 질소 존재하에 천천히 교반하였다. 이후 상기 혼합물은 상온에서 30분 동안 더 교반시키고 건조된 디메틸포름아마이드 5ml에 있는 4-플루오로-3-(트리플로오로메틸)벤즈알데히드(1.2g, 7.8mmol)을 10분 동안 첨가하였다. 이후 상기 반응 혼합물을 초기물질들이 사라질 때까지 18시간 동안 상온에서 교반하였다. 이후 상기 혼합물에 얼음물 20ml을 첨가하고 에틸아세테이트와 물을 사용하여 추출하였다. 유기층은 물로 여러번 세척한 다음 무수 황 마그네슘을 이용하여 건조시켰고, 여과 및 증발시켰다. 잔여 오일은 실리카 겔 컬럼크로마토그래피를 수행하였으며, 이때 용출용매로 헥산 및 에틸아세테이트가 20:1로 혼합된 용매를 사용하였다. 그 결과, 4-((메틸시클로헥실) 메톡시)-3-(트리플로메틸)벤즈알데히드(1.64g, 87% 수율)의 중간체를 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[4-((4-메틸시클로헥실)메톡시)-3-(트리플루메틸)벤질리덴]티아졸리딘-2,4-디온( 5-[4-((4-metylcyclohexyl)methoxy)-3-(trifluromethyl)benzylidene]thiazolidine-2,4-dione)(1.02 g, 76.1% 수율)을 수득하였다. 상기 유도체 65 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.602 (s, 1H), 7.878 (s, 1H), 7.829(s, 1H), 7.805 (d, J = 8.4 Hz, 1H), 7.101 (d, J = 8.4 Hz, 1H), 4.117 (d, J = 6.6 Hz, 1H), 4.016 (d, J = 6.6 Hz, 1H), 1.685-1.907 (m, 4H), 1.454-1.523 (m, 4H), 1.083-1.122(m, 2H), 0.927 (d, J = 6.9 Hz, 3H)이었다.To sodium hydride (342.2 mg, 8.58 mmol, 60% dispersion oil), 4-methyl-1-cyclohexanemethanol (1 g, 7.8 mmol) present in dried dimethylformamide (30 ml) was added, followed by nitrogen at room temperature. Under slow stirring. The mixture was then further stirred at room temperature for 30 minutes and 4-fluoro-3- (trifluoromethyl) benzaldehyde (1.2 g, 7.8 mmol) in 5 ml of dried dimethylformamide was added for 10 minutes. The reaction mixture was then stirred at room temperature for 18 hours until the initial materials disappeared. Thereafter, 20 ml of ice water was added to the mixture, followed by extraction using ethyl acetate and water. The organic layer was washed several times with water and then dried over anhydrous magnesium sulfate, filtered and evaporated. The remaining oil was subjected to silica gel column chromatography, and a solvent in which hexane and ethyl acetate were mixed at 20: 1 was used as an elution solvent. As a result, an intermediate of 4-((methylcyclohexyl) methoxy) -3- (triflomethyl) benzaldehyde (1.64 g, 87% yield) was obtained, and the obtained intermediate product was then obtained as a derivative of Example 51. A 5- [4-((4-methylcyclohexyl) represented by the above formula was carried out in the same manner, except that it was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the preparation process. Methoxy) -3- (triflumethyl) benzylidene] thiazolidine-2,4-dione (5- [4-((4-metylcyclohexyl) methoxy) -3- (trifluromethyl) benzylidene] thiazolidine-2,4 -dione) (1.02 g, 76.1% yield) was obtained. The derivative 65 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.602 (s, 1H), 7.878 (s, 1H), 7.829 (s, 1H), 7.805 (d, J = 8.4 Hz, 1H ), 7.101 (d, J = 8.4 Hz, 1H), 4.117 (d, J = 6.6 Hz, 1H), 4.016 (d, J = 6.6 Hz, 1H), 1.685-1.907 (m, 4H), 1.454-1.523 (m, 4H), 1.083-1.122 (m, 2H), 0.927 (d, J = 6.9 Hz, 3H).
<실시예 66>Example 66
본 발명에 따른 유도체 66의 제조Preparation of the derivative 66 according to the invention
하기 화학식으로 나타내는 유도체 66을 다음과 같은 방법으로 제조하였다.      Derivative 66 represented by the following formula was prepared in the following manner.
<유도체 66의 화학식>      <Formula of derivative 66>
Figure PCTKR2009007995-appb-I000071
Figure PCTKR2009007995-appb-I000071
상온에서 시약 등급의 메탄올 10ml에 용해된 4-히드록시메틸-1-시클로헥신 카르복실산(1g, 6.3mmol) 용액에 티오닐 클로라이드(1.50g, 12.6mmol)를 한방울씩 떨어뜨렸다. 상기 혼합 용액은 밤새도록 가열처리하여 환류시켰고, 반응 혼합액은 감압하에서 농축시켰으며, 이후 실리카 겔 크로마토그래피를 통해 0.78g 4-히드록시메틸-1-시클로헥산카르복실산염(71.6%의 수율)을 수득하였다. 또한, 실리카 겔 컬럼 크로마토그래피를 통해 헥산 및 에틸아세테이트가 10:1로 혼합된 용출 용매를 사용하여 4-((4-아세틸시클로헥실)메톳기)벤즈알데히드 0.86g을 수득하였다(76.8% 수율). 이후 상기에서 수득한 2가지의 화합물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 메틸-4-((4-((2,4-디옥소티아졸리딘-5-일이덴)메틸)페녹시)시클로헥산카르복실레이트(methyl-4-((4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)methyl)cyclohexanecarboxylate)(1.03 g, 74.1% 수율)을 수득하였고, 상기 수득한 유도체 66의 화합물은 1H NMR (300 MHz, DMSO-d 6) δ 12.482 (s, 1H), 7.736 (s, 1H), 7.552 (d, J = 15.9 Hz, 4H), 7.580 (t, J = 9.0 Hz, 2H), 7.103 (d, J = 9.0 Hz, 2H), 3.904 (d, J = 6.6 Hz, 2H), 3.610 (s, 3H), 2.604-2.623 (m, 1H), 1.891-1.984 (m, 3H), 1.450-1.675 (m, 4H), 1.273-1.342 (m, 2H)이었다.Thionyl chloride (1.50 g, 12.6 mmol) was added dropwise to a solution of 4-hydroxymethyl-1-cyclohexine carboxylic acid (1 g, 6.3 mmol) dissolved in 10 ml of reagent grade methanol at room temperature. The mixed solution was heated to reflux overnight, the reaction mixture was concentrated under reduced pressure, and then 0.78 g 4-hydroxymethyl-1-cyclohexanecarboxylate (71.6% yield) was obtained by silica gel chromatography. Obtained. Also, silica gel column chromatography gave 0.86 g of 4-((4-acetylcyclohexyl) methic group) benzaldehyde (76.8% yield) using an eluting solvent in which hexane and ethyl acetate were mixed at 10: 1. Thereafter, the two compounds obtained above were used in the same manner as in Example 2, except that 4- (2-cyclomethoxy) -3-methylbenzaldehyde was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde. Methyl-4-((4-((2,4-dioxothiazolidine-5-ylidene) methyl) phenoxy) cyclohexanecarboxylate (methyl-4-((4-(( 2,4-dioxothiazolidine-5-ylidene) methyl) phenoxy) methyl) cyclohexanecarboxylate) (1.03 g, 74.1% yield) was obtained and the obtained compound 66 was obtained by 1 H NMR (300 MHz, DMSO- d 6 ). δ 12.482 (s, 1H), 7.736 (s, 1H), 7.552 (d, J = 15.9 Hz, 4H), 7.580 (t, J = 9.0 Hz, 2H), 7.103 (d, J = 9.0 Hz, 2H) , 3.904 (d, J = 6.6 Hz, 2H), 3.610 (s, 3H), 2.604-2.623 (m, 1H), 1.891-1.984 (m, 3H), 1.450-1.675 (m, 4H), 1.273-1.342 (m, 2H).
<실시예 67><Example 67>
본 발명에 따른 유도체 67의 제조Preparation of the derivative 67 according to the invention
하기 화학식으로 나타내는 유도체 67을 다음과 같은 방법으로 제조하였다.      Derivative 67 represented by the following formula was prepared in the following manner.
<유도체 67의 화학식>      <Formula of derivative 67>
Figure PCTKR2009007995-appb-I000072
Figure PCTKR2009007995-appb-I000072
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올을 1g, 7.8mmol 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 이소바닐린(1.19g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-(2-시클로헥실에톡시)-4-메톡시벤즈알데히드 1.68g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 82.1%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-(2-시클로헥실에톡시)4-메톡시벤질리덴)티아졸리디온-2,4-디온(5-(3-(2-cyclohexylethoxy)-4-methoxybenzylidene)thiazolidine-2,4-dione)(1.24 g, 87.2% 수율)을 수득하였으며, 상기 수득한 유도체 67의 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.436 (s, 1H), 8.165 (s, 1H), 7.941 (d, J = 9.5 Hz, 1H), 7.661 (s, 1H), 7.273 (d, J = 9.5 Hz, 1H), 4.233 (t, J = 13.5 Hz, 2H), 3.864 (s, 3H), 1.682-1.759 (m, 7H), 1.442-1.586 (m, 1H), 1.182-1.242 (m, 3H), 0.896-0.926 (m, 2H)이었다.In preparing the derivative of Example 51, 1 g, 7.8 mmol of cyclohexane ethanol was used instead of cyclohexane methanol, and isovaniline (1.19 g, 7.8 mmol) was used instead of 4-hydroxy-3-methylbenzaldehyde. The same procedure was followed to obtain 1.68 g of the intermediate product 3- (2-cyclohexylethoxy) -4-methoxybenzaldehyde, except that phenylphosphoryne was used in an amount of 2.25 g and 8.58 mmol, wherein the intermediate The yield of the product was 82.1%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3- (2-cyclohexylethoxy) 4-methoxybenzylidene) thiazolidione-2,4-dione (5- (3- (2-cyclohexylethoxy) -4-methoxybenzylidene) thiazolidine-2,4 -dione) (1.24 g, 87.2% yield), the obtained compound of derivative 67 was 1 H NMR (300 MHz, DMSO- d 6 ) δ12.436 (s, 1H), 8.165 (s, 1H) , 7.941 (d, J = 9.5 Hz, 1H), 7.661 (s, 1H), 7.273 (d, J = 9.5 Hz, 1H), 4.233 (t, J = 13.5 Hz, 2H), 3.864 (s, 3H) , 1.682-1.759 (m, 7H), 1.442-1.586 (m, 1H), 1.182-1.242 (m, 3H), 0.896-0.926 (m, 2H).
<실시예 68><Example 68>
본 발명에 따른 유도체 68의 제조Preparation of the derivative 68 according to the invention
하기 화학식으로 나타내는 유도체 68을 다음과 같은 방법으로 제조하였다.      Derivative 68 represented by the following formula was prepared in the following manner.
<유도체 68의 화학식>      <Formula of derivative 68>
Figure PCTKR2009007995-appb-I000073
Figure PCTKR2009007995-appb-I000073
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 벤질알콜(1g, 9.2mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.44g, 9.2mmol)를 사용하며, 트리페닐포스피린을 2.65g, 10.12mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(벤질옥시)-3-클로로벤즈알데히드 1.76g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 77.2%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(벤질옥시)-3-클로로벤질리덴)티아졸리딘-2,4-디온(5-(4-(benzyloxy)-3-chlorobenzylidene)thiazolidine-2,4-dione) (1.21 g, 86.4% 수율)을 수득하였고, 상기 수득한 68 유도체 화합물은 1H NMR (300 MHz, DMSO-d 6) δ8.024 (s, 1H), 7.936 (s, 1H), 7.747 (d, J = 10.2 Hz, 1H), 7.324-7.479 (m, 5H), 7.093 (d, J = 10.2 Hz, 1H), 5.259 (s, 2H)이었다. Benzyl alcohol (1 g, 9.2 mmol) was used instead of cyclohexane methanol in the preparation of the derivative of Example 51, and 3-chloro-4-hydroxy benzaldehyde (1.44 g, instead of 4-hydroxy-3-methylbenzaldehyde). 9.2 mmol) and 1.76 g of the intermediate product 4- (benzyloxy) -3-chlorobenzaldehyde were obtained using the same method except that triphenylphosphine was used in an amount of 2.65 g and 10.12 mmol, The yield of this intermediate product was 77.2%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4- (benzyloxy) -3-chlorobenzylidene) thiazolidine-2,4-dione (5- (4- (benzyloxy) -3-chlorobenzylidene) thiazolidine-2,4-dione) (1.21 g , 86.4% yield), and the 68 derivative compound obtainedOneH NMR (300 MHz, DMSO-d                 6) δ 8.024 (s, 1H), 7.936 (s, 1H), 7.747 (d,J = 10.2 Hz, 1H), 7.324-7.479 (m, 5H), 7.093 (d,J = 10.2 Hz, 1H), 5.259 (s, 2H).
<실시예 69><Example 69>
본 발명에 따른 유도체 69의 제조Preparation of the derivative 69 according to the invention
하기 화학식으로 나타내는 유도체 69를 다음과 같은 방법으로 제조하였다.      Derivative 69 represented by the following formula was prepared in the following manner.
<유도체 69의 화학식>      <Formula of derivative 69>
Figure PCTKR2009007995-appb-I000074
Figure PCTKR2009007995-appb-I000074
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-페닐에탄올(1g, 8.2mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.28g, 8.2mmol)를 사용하며, 트리페닐포스피린을 2.37g, 9.02mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-페닐에톡시벤즈알데히드 1.69g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 79.3%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-페닐에톡시벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-4-phenylethoxybenzylidene)thiazolidine-2,4-dione) (1.19 g, 86.2% 수율)을 수득하였고, 수득한 상기 유도체 69 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.547 (s, 1H), 7.894 (s, 1H), 7.694 (s, 1H), 7.533 (d, J = 11.1 Hz, 1H), 7.311-7.348 (m, 5H), 7.248 (d, J = 11.1 Hz, 1H), 4.367 ( t,J = 13.5 Hz, 2H), 3.109 (t, J = 13.5 Hz, 2H)이었다.In preparing the derivative of Example 51, 2-phenylethanol (1 g, 8.2 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxybenzaldehyde (1.28) instead of 4-hydroxy-3-methylbenzaldehyde. g, 8.2 mmol) and 1.69 g of the intermediate product 3-chloro-4-phenylethoxybenzaldehyde were obtained using the same method except that triphenylphosphine was used in an amount of 2.37 g and 9.02 mmol. In this case, the yield of the intermediate product was 79.3%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione (5- (3-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione) (1.19 g, 86.2% Yield), and the obtained derivative 69 compound was obtained by 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.547 (s, 1H), 7.894 (s, 1H), 7.694 (s, 1H), 7.533 ( d, J = 11.1 Hz, 1H), 7.311-7.348 (m, 5H), 7.248 (d, J = 11.1 Hz, 1H), 4.367 (t, J = 13.5 Hz, 2H), 3.109 (t, J = 13.5 Hz, 2H).
<실시예 70><Example 70>
본 발명에 따른 유도체 70의 제조Preparation of the derivative 70 according to the invention
하기 화학식으로 나타내는 유도체 70을 다음과 같은 방법으로 제조하였다.      A derivative 70 represented by the following formula was prepared in the following manner.
<유도체 70의 화학식>      <Formula of derivative 70>
Figure PCTKR2009007995-appb-I000075
Figure PCTKR2009007995-appb-I000075
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 3-페닐-1-프로판올(1g, 7.3mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.14g, 7.3mmol)를 사용하며, 트리페닐포스피린을 2.11g, 8.03mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(3-페닐프로폭시)벤즈알데히드 1.48g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 73.6%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-(3-페닐프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-4-(3-phenylpropoxy)benzylidene)thiazolidine-2,4-dione)(1.13 g, 83.1% 수율)을 수득하였다. 상기 수득한 유도체 70 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.538 (s, 1H), 7.714 (s, 1H), 7.706 (s, 1H), 7.533 (d, J = 10.8 Hz, 1H), 7.158 7.311 (m, 6H), 4.143 ( t, J = 12.3 Hz, 2H), 2.802 (t, J = 12.8 Hz, 2H), 2.022-2.093 (m, 2H)이었다.3-phenyl-1-propanol (1 g, 7.3 mmol) was used instead of cyclohexanemethanol in the preparation of the derivative of Example 51, and 3-chloro-4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Benzaldehyde (1.14 g, 7.3 mmol) was used, and the intermediate product 3-chloro-4- (3-phenylpropoxy was used in the same manner, except that triphenylphosphine was used in an amount of 2.11 g and 8.03 mmol. 1.48 g of benzaldehyde was obtained, with a yield of 73.6% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3-chloro-4- (3-phenylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro-4- (3-phenylpropoxy) benzylidene) thiazolidine-2,4 -dione) (1.13 g, 83.1% yield) was obtained. The obtained derivative 70 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.538 (s, 1H), 7.714 (s, 1H), 7.706 (s, 1H), 7.533 (d, J = 10.8 Hz , 1H), 7.158 7.311 (m, 6H), 4.143 (t, J = 12.3 Hz, 2H), 2.802 (t, J = 12.8 Hz, 2H), 2.022-2.093 (m, 2H).
<실시예 71><Example 71>
본 발명에 따른 유도체 71의 제조Preparation of Derivative 71 According to the Invention
하기 화학식으로 나타내는 유도체 71을 다음과 같은 방법으로 제조하였다.      Derivative 71 represented by the following formula was prepared in the following manner.
<유도체 71의 화학식>      <Formula of derivative 71>
Figure PCTKR2009007995-appb-I000076
Figure PCTKR2009007995-appb-I000076
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-페닐-1-부판올(1g, 6.7mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.05g, 6.7mmol)를 사용하며, 트리페닐포스피린을 1.93g, 7.37mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(4-페닐부톡시)벤즈알데히드 1.43g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 74.5%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-(4-페닐부톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-4-(4-phenylbutoxy)benzylidene)thiazolidine-2,4-dione)(1.04g, 77.6% 수율)을 수득하였고, 상기 수득한 유도체 71 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.577 (s, 1H), 7.720 (s, 1H), 7.693 (s, 1H), 7.529 (d, J = 10.5 Hz, 1H), 7.135-7.304 (m, 6H), 4.155 (t, J = 5.7 Hz, 2H), 2.671 (t, J = 7.2 Hz, 2H), 1.741-1.761 (m, 4H)이었다. In preparing the derivative of Example 51, 4-phenyl-1-butanol (1 g, 6.7 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Roxybenzaldehyde (1.05 g, 6.7 mmol) was used, and the intermediate product 3-chloro-4- (4-phenyl moiety was obtained in the same manner except that triphenylphosphine was used in an amount of 1.93 g and 7.37 mmol. 1.43 g of oxy) benzaldehyde was obtained, with a yield of 74.5% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3-chloro-4- (4-phenylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro-4- (4-phenylbutoxy) benzylidene) thiazolidine-2,4 -dione) (1.04 g, 77.6% yield), the resulting derivative 71 compoundOneH NMR (300 MHz, DMSO-d                 6) δ 12.577 (s, 1H), 7.720 (s, 1H), 7.693 (s, 1H), 7.529 (d,J = 10.5 Hz, 1H), 7.135-7.304 (m, 6H), 4.155 (t,J = 5.7 Hz, 2H), 2.671 (t,J = 7.2 Hz, 2H), 1.741-1.761 (m, 4H).
<실시예 72><Example 72>
본 발명에 따른 유도체 72의 제조Preparation of the derivative 72 according to the invention
하기 화학식으로 나타내는 유도체 72를 다음과 같은 방법으로 제조하였다.      Derivative 72 represented by the following formula was prepared in the following manner.
<유도체 72의 화학식>      <Formula of derivative 72>
Figure PCTKR2009007995-appb-I000077
Figure PCTKR2009007995-appb-I000077
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 벤질알콜(1g, 9.2mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.44g, 9.2mmol)를 사용하며, 트리페닐포스피린을 2.65g, 10.12mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-(벤질옥시)-2-클로로벤즈알데히드 1.69g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 74.1%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-(벤질옥시)-2-클로로벤질리덴)티아졸리딘-2,4-디온(5-(3-(benzyloxy)-2-chlorobenzylidene)thiazolidine-2,4-dione)(1.05 g, 75% 수율)을 수득하였다. 상기 수득한 유도체 72 화합물은 1H NMR (300 MHz, DMSO-d 6) δ7.753 (s, 1H), 7.498 (d, J = 7.8 Hz, 1H), 7.339-7.413 (m, 6H), 7.241 (d, J = 7.8 Hz, 1H), 5.243 (s, 2H)이었다.Benzyl alcohol (1 g, 9.2 mmol) was used instead of cyclohexane methanol in the preparation of the derivative of Example 51, and 2-chloro-3-hydroxy benzaldehyde (1.44 g, instead of 4-hydroxy-3-methylbenzaldehyde). 9.2 mmol) and 1.69 g of intermediate product 3- (benzyloxy) -2-chlorobenzaldehyde were obtained using the same method except that triphenylphosphine was used in an amount of 2.65 g and 10.12 mmol, The yield of this intermediate product was 74.1%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3- (benzyloxy) -2-chlorobenzylidene) thiazolidine-2,4-dione (5- (3- (benzyloxy) -2-chlorobenzylidene) thiazolidine-2,4-dione) (1.05 g , 75% yield). The obtained derivative 72 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ7.753 (s, 1H), 7.498 (d, J = 7.8 Hz, 1H), 7.339-7.413 (m, 6H), 7.241 (d, J = 7.8 Hz, 1H), 5.243 (s, 2H).
<실시예 73><Example 73>
본 발명에 따른 유도체 73의 제조Preparation of the derivative 73 according to the invention
하기 화학식으로 나타내는 유도체 73을 다음과 같은 방법으로 제조하였다.      Derivative 73 represented by the following formula was prepared in the following manner.
<유도체 73의 화학식>      <Formula of derivative 73>
Figure PCTKR2009007995-appb-I000078
Figure PCTKR2009007995-appb-I000078
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-페닐에탄올(1g, 8.2mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.28g, 8.2mmol)를 사용하며, 트리페닐포스피린을 2.37g, 9.02mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-페닐에톡시벤즈알데히드 1.60g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 75.1%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-페닐에톡시벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-phenylethoxybenzylidene)thiazolidine-2,4-dione)(1.07 g, 77.5% 수율)을 수득하였다. 상기 수득한 유도체 73 화합물은 1H NMR (300 MHz, DMSO-d 6) δ7.894 (s, 1H), 7.459 (d, J = 7.8 Hz, 1H), 7.141-7.495 (m, 6H), 7.164 (d, J= 7.8 Hz, 1H), 4.328 (t, J= 13.5 Hz, 2H), 3.107 (t, J = 13.2 Hz, 2H)이었다.In preparing the derivative of Example 51, 2-phenylethanol (1 g, 8.2 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxybenzaldehyde (1.28) instead of 4-hydroxy-3-methylbenzaldehyde. g, 8.2 mmol), and 1.60 g of the intermediate product 2-chloro-3-phenylethoxybenzaldehyde was obtained using the same method except that triphenylphosphine was used in an amount of 2.37 g and 9.02 mmol. In this case, the yield of the intermediate product was 75.1%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3-phenylethoxybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-3-phenylethoxybenzylidene) thiazolidine-2,4-dione) (1.07 g, 77.5% Yield). The obtained derivative 73 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.894 (s, 1 H), 7.459 (d, J = 7.8 Hz, 1H), 7.141-7.495 (m, 6H), 7.164 (d, J = 7.8 Hz, 1H), 4.328 (t, J = 13.5 Hz, 2H), 3.107 (t, J = 13.2 Hz, 2H).
<실시예 74><Example 74>
본 발명에 따른 유도체 74의 제조Preparation of the derivative 74 according to the invention
하기 화학식으로 나타내는 유도체 74를 다음과 같은 방법으로 제조하였다.      Derivative 74 represented by the following formula was prepared in the following manner.
<유도체 74의 화학식>      <Formula of derivative 74>
Figure PCTKR2009007995-appb-I000079
Figure PCTKR2009007995-appb-I000079
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-페닐-1-부탄올(1g, 6.7mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.05g, 6.7mmol)를 사용하며, 트리페닐포스피린을 1.93g, 7.37mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(4-페닐부톡시)벤즈알데히드 1.40g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 72.9%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(4-페닐부톡시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(4-phenylbutoxy)benzylidene)thiazolidine-2,4-dione)(1.10 g, 82.1% 수율)을 수득하였다. 상기 수득한 유도체 74 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.719 (s, 1H), 7.932 (s, 1H), 7.474 (t, J= 8.1 Hz, 1H ), 7.151-7.303 (m, 7H), 4.145 (t, J = 5.1 Hz, 2H), 2.658 (t, J = 5.3 Hz, 2H), 2.084 (t, J = 2.7 Hz, 4H)이었다.In preparing the derivative of Example 51, 4-phenyl-1-butanol (1 g, 6.7 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Benzaldehyde (1.05 g, 6.7 mmol) was used, and the intermediate product 2-chloro-3- (4-phenylbutoxy was used in the same manner, except that triphenylphosphine was used in an amount of 1.93 g and 7.37 mmol. 1.40 g of benzaldehyde was obtained, with a yield of 72.9% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3- (4-phenylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (4-phenylbutoxy) benzylidene) thiazolidine-2,4 -dione) (1.10 g, 82.1% yield) was obtained. The obtained derivative 74 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.719 (s, 1H), 7.932 (s, 1H), 7.474 (t, J = 8.1 Hz, 1H), 7.151-7.303 (m, 7H), 4.145 (t, J = 5.1 Hz, 2H), 2.658 (t, J = 5.3 Hz, 2H), 2.084 (t, J = 2.7 Hz, 4H).
<실시예 75><Example 75>
본 발명에 따른 유도체 75의 제조Preparation of Derivative 75 According to the Invention
하기 화학식으로 나타내는 유도체 75를 다음과 같은 방법으로 제조하였다.      Derivative 75 represented by the following formula was prepared in the following manner.
<유도체 75의 화학식>      <Formula of derivative 75>
Figure PCTKR2009007995-appb-I000080
Figure PCTKR2009007995-appb-I000080
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 3-페닐-1-프로판올(1g, 7.3mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.14g, 7.3mmol)를 사용하며, 트리페닐포스피린을 2.11g, 8.03mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(3-페닐프로폭시)벤즈알데히드 1.30g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 64.6%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(3-페닐프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(3-phenylpropoxy)benzylidene)thiazolidine-2,4-dione)(1.12 g, 82.4% 수율)을 수득하였다. 상기 수득한 유도체 75 화합물은 1H NMR (300 MHz, DMSO-d 6) δ7.927 (s, 1H), 7.464 (t, J = 7.8 Hz, 1H), 7.151 7.312 (m, 7H), 4.109 (t, J = 12.3 Hz, 2H), 2.813 (t, J = 12.5 Hz, 2H), 2.084 (t, J = 13.2 Hz, 2H)이었다.In preparing the derivative of Example 51, 3-phenyl-1-propanol (1 g, 7.3 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Benzaldehyde (1.14 g, 7.3 mmol) was used, and the intermediate product 2-chloro-3- (3-phenylpropoxy was obtained using the same method except that triphenylphosphine was used in an amount of 2.11 g and 8.03 mmol. 1.30 g of benzaldehyde was obtained, with a yield of 64.6% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3- (3-phenylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (3-phenylpropoxy) benzylidene) thiazolidine-2,4 -dione) (1.12 g, 82.4% yield) was obtained. The obtained derivative 75 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ7.927 (s, 1H), 7.464 (t, J = 7.8 Hz, 1H), 7.151 7.312 (m, 7H), 4.109 ( t, J = 12.3 Hz, 2H), 2.813 (t, J = 12.5 Hz, 2H), 2.084 (t, J = 13.2 Hz, 2H).
<실시예 76><Example 76>
본 발명에 따른 유도체 76의 제조Preparation of the derivative 76 according to the invention
하기 화학식으로 나타내는 유도체 76을 다음과 같은 방법으로 제조하였다.      Derivative 76 represented by the following formula was prepared in the following manner.
<유도체 76의 화학식>      <Formula of derivative 76>
Figure PCTKR2009007995-appb-I000081
Figure PCTKR2009007995-appb-I000081
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-히드록시메틸바이페닐(1g, 5.4mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시벤즈알데히드(0.66g, 5.4mmol)를 사용하며, 트리페닐포스피린을 1.56g, 5.94mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(바이페닐-4-일메톡시)벤즈알데히드 1.20g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 76.9%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(바이페닐-4-일베톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-(Biphenyl-4-ylmethoxy)benzylidene)thiazolidine-2,4-dione)(1.12 g, 83.6% 수율)을 수득하였다. 상기 수득한 유도체 76 화합물은 1H NMR (300 MHz, DMSO-d 6) δ 12.513 (s, 1H), 7.735 (s, 1H), 7.703 (t, J = 15.9 Hz, 4H), 7.580 (t, J = 15.9 Hz, 4H), 7.486 (t, J = 14.7 Hz, 2H), 7.384 (m, 1H), 7.206 (d, J = 8.7 Hz, 2H), 5.235 (s, 2H)이었다.In preparing the derivative of Example 51, 4-hydroxymethylbiphenyl (1 g, 5.4 mmol) was used instead of cyclohexanemethanol, and 4-hydroxybenzaldehyde (0.66 g instead of 4-hydroxy-3-methylbenzaldehyde. , 5.4 mmol), and 1.20 g of intermediate product 4- (biphenyl-4-ylmethoxy) benzaldehyde was obtained using the same method except that triphenylphosphine was used in an amount of 1.56 g and 5.94 mmol. Wherein the yield of the intermediate product was 76.9%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4- (biphenyl-4-ylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (Biphenyl-4-ylmethoxy) benzylidene) thiazolidine-2,4-dione) ( 1.12 g, 83.6% yield). The obtained derivative 76 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.513 (s, 1H), 7.735 (s, 1H), 7.703 (t, J = 15.9 Hz, 4H), 7.580 (t, J = 15.9 Hz, 4H), 7.486 (t, J = 14.7 Hz, 2H), 7.384 (m, 1H), 7.206 (d, J = 8.7 Hz, 2H), 5.235 (s, 2H).
<실시예 77><Example 77>
본 발명에 따른 유도체 77의 제조Preparation of the derivative 77 according to the invention
하기 화학식으로 나타내는 유도체 77을 다음과 같은 방법으로 제조하였다.      Derivative 77 represented by the following formula was prepared in the following manner.
<유도체 77의 화학식>      <Formula of derivative 77>
Figure PCTKR2009007995-appb-I000082
Figure PCTKR2009007995-appb-I000082
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올(1g, 7.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-5-플루오르-4-히드록시벤즈알데히드(1.36g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-5-플루오르-4-(2-시클로헥실에톡시)벤즈알데히드 1.79g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 80.6%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-5-플루오로-4-(2-시클로헥실에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-5-fluoro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione) (1.0 g, 75.4% 수율)을 수득하였다. 상기 수득한 유도체 77 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.061 (s, 1H), 7.950 (s, 1H), 7.532 (s, 1H), 7.488 (s, 2H), 4.178 (t, J = 15.5 Hz, 2H), 1.588-1.749 (m, 7H), 1.505-1.580 (m, 1H), 1.107-1.237 (m, 3H), 0.903-0.980 (m, 2H)이었다.In preparing the derivative of Example 51, cyclohexaneethanol (1 g, 7.8 mmol) was used instead of cyclohexane methanol, and 3-chloro-5-fluoro-4-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Benzaldehyde (1.36 g, 7.8 mmol) was used, and the intermediate product 3-chloro-5-fluoro-4- (2) was obtained using the same method except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.79 g of -cyclohexylethoxy) benzaldehyde were obtained, wherein the yield of the intermediate product was 80.6%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3-chloro-5-fluoro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro-5-fluoro-4- (2 -cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione) (1.0 g, 75.4% yield) was obtained. The obtained derivative 77 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ12.061 (s, 1H), 7.950 (s, 1H), 7.532 (s, 1H), 7.488 (s, 2H), 4.178 (t, J = 15.5 Hz, 2H), 1.588-1.749 (m, 7H), 1.505-1.580 (m, 1H), 1.107-1.237 (m, 3H), 0.903-0.980 (m, 2H).
<실시예 78><Example 78>
본 발명에 따른 유도체 78의 제조Preparation of the derivative 78 according to the invention
하기 화학식으로 나타내는 유도체 78을 다음과 같은 방법으로 제조하였다.      Derivative 78 represented by the following formula was prepared in the following manner.
<유도체 78의 화학식>      <Formula of derivative 78>
Figure PCTKR2009007995-appb-I000083
Figure PCTKR2009007995-appb-I000083
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올(1g, 7.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시-5-메톡시벤즈알데히드(1.46g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(2-시클로헥실에톡시)-5-메톡시벤즈알데히드 1.8g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 77.9%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-(2-시클로헥실에톡시)-5-메톡시벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-4-(2-cyclohexylethoxy)-5-methoxybenzylidene)thiazolidine-2,4-dione) (1.12 g, 84.2% 수율)을 수득하였다. 상기 수득한 유도체 78 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.656 (s, 1H), 7.738 (s, 1H), 7.262 (s, 1H), 7.239 (s, 1H), 4.043 (t, J = 12.6 Hz, 2H), 3.872(s, 3H), 1.557-1.754 (m, 8H), 1.144-1.239(m, 3H), 0.891-0.964 (m, 2H)이었다.In preparing the derivative of Example 51, cyclohexaneethanol (1 g, 7.8 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxy-5-methicyl instead of 4-hydroxy-3-methylbenzaldehyde. Oxygenbenzaldehyde (1.46 g, 7.8 mmol) was used, and the intermediate product 3-chloro-4- (2-cyclohexyl was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.8 g of ethoxy) -5-methoxybenzaldehyde was obtained, wherein the yield of the intermediate product was 77.9%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3-chloro-4- (2-cyclohexylethoxy) -5-methoxybenzylidene) thiazolidine-2,4-dione (5- (3-chloro-4- (2-cyclohexylethoxy)- 5-methoxybenzylidene) thiazolidine-2,4-dione) (1.12 g, 84.2% yield) was obtained. The obtained derivative 78 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.656 (s, 1H), 7.738 (s, 1H), 7.262 (s, 1H), 7.239 (s, 1H), 4.043 (t, J = 12.6 Hz, 2H), 3.872 (s, 3H), 1.557-1.754 (m, 8H), 1.144-1.239 (m, 3H), 0.891-0.964 (m, 2H).
<실시예 79><Example 79>
본 발명에 따른 유도체 79의 제조Preparation of the derivative 79 according to the invention
하기 화학식으로 나타내는 유도체 79를 다음과 같은 방법으로 제조하였다.      Derivative 79 represented by the following formula was prepared in the following manner.
<유도체 79의 화학식>      <Formula of derivative 79>
Figure PCTKR2009007995-appb-I000084
Figure PCTKR2009007995-appb-I000084
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올(1g, 7.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-히드록시-4-니트로벤즈알데히드(1.30g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-(2-시클로헥실에톡시)-4-니트로벤즈알데히드 1.78g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 82.4%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-(2-시클로헥실에톡시)-4-니트로벤질리덴)티아졸리딘-2,4-디온(5-(3-(2-cyclohexylethoxy)-4-nitrobenzylidene)thiazolidine-2,4-dione)(1.24 g, 87% 수율)을 수득하였다. 상기 수득한 유도체 79 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.644 (s, 1H), 8.003 (d, J = 8.4 Hz, 1H), 7.799 (s, 1H), 7.611 (s, 1H), 7.273 (s, J = 8.4 Hz, 1H), 4.255 (t, J = 13.5 Hz, 2H), 1.618-1.746 (m, 7H), 1.401-1.546 (m, 1H), 1.144-1.323 (m, 3H), 0.928-0.1.006 (m, 2H)이었다.In preparing the derivative of Example 51, cyclohexaneethanol (1 g, 7.8 mmol) was used instead of cyclohexane methanol, and 3-hydroxy-4-nitrobenzaldehyde (1.30 g) instead of 4-hydroxy-3-methylbenzaldehyde. , 7.8 mmol), and the intermediate product 3- (2-cyclohexylethoxy) -4-nitrobenzaldehyde 1.78 using the same method except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. g was obtained, wherein the yield of the intermediate product was 82.4%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3- (2-cyclohexylethoxy) -4-nitrobenzylidene) thiazolidine-2,4-dione (5- (3- (2-cyclohexylethoxy) -4-nitrobenzylidene) thiazolidine-2, 4-dione) (1.24 g, 87% yield) was obtained. The obtained derivative 79 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.644 (s, 1H), 8.003 (d, J = 8.4 Hz, 1H), 7.799 (s, 1H), 7.611 (s , 1H), 7.273 (s, J = 8.4 Hz, 1H), 4.255 (t, J = 13.5 Hz, 2H), 1.618-1.746 (m, 7H), 1.401-1.546 (m, 1H), 1.144-1.323 ( m, 3H), 0.928-0.1.006 (m, 2H).
<실시예 80><Example 80>
본 발명에 따른 유도체 80의 제조Preparation of Derivative 80 According to the Invention
하기 화학식으로 나타내는 유도체 80을 다음과 같은 방법으로 제조하였다.      Derivative 80 represented by the following formula was prepared in the following manner.
<유도체 80의 화학식>      <Formula of derivative 80>
Figure PCTKR2009007995-appb-I000085
Figure PCTKR2009007995-appb-I000085
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올(1g, 7.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시-4-메톡시벤즈알데히드(1.46g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(2-시클로헥실에톡시)-4-메톡시벤즈알데히드 2.03g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 88.3%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(2-시클로헥실에톡시)-4-메톡시벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(2-cyclohexylethoxy)-4-methoxybenzylidene)thiazolidine-2,4-dione) (1.04 g, 78.1% 수율)을 수득하였다. 상기 수득한 유도체 80 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.743 (s, 1H), 7.319 (s, J = 8.7 Hz, 1H), 7.247(s, J = 8.7Hz, 1H), 4.007 (t, J = 12.6 Hz, 2H), 3.890 (s, 3H), 1.516-1.764 (m, 8H), 1.109-1.245 (m, 3H), 0.894-0.970 (m, 2H)이었다.In preparing the derivative of Example 51, cyclohexaneethanol (1 g, 7.8 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxy-4-methicyl instead of 4-hydroxy-3-methylbenzaldehyde. Oxygenbenzaldehyde (1.46 g, 7.8 mmol) was used, and the intermediate product 2-chloro-3- (2-cyclohexyl was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 2.03 g of ethoxy) -4-methoxybenzaldehyde was obtained with a yield of 88.3% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3- (2-cyclohexylethoxy) -4-methoxybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (2-cyclohexylethoxy)- 4-methoxybenzylidene) thiazolidine-2,4-dione) (1.04 g, 78.1% yield) was obtained. The obtained derivative 80 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.743 (s, 1H), 7.319 (s, J = 8.7 Hz, 1H), 7.247 (s, J = 8.7 Hz, 1H ), 4.007 (t, J = 12.6 Hz, 2H), 3.890 (s, 3H), 1.516-1.764 (m, 8H), 1.109-1.245 (m, 3H), 0.894-0.970 (m, 2H).
<실시예 81><Example 81>
본 발명에 따른 유도체 81의 제조Preparation of the derivative 81 according to the invention
하기 화학식으로 나타내는 유도체 81을 다음과 같은 방법으로 제조하였다.      Derivative 81 represented by the following formula was prepared in the following manner.
<유도체 81의 화학식>      <Formula of derivative 81>
Figure PCTKR2009007995-appb-I000086
Figure PCTKR2009007995-appb-I000086
건조된 디메틸포름아마이드 (30ml)에 용해된 시클로헥산에탄올(1g, 7.8mmol) 용액에 상온의 질소 조건하에서 수소화 나트륨(343.2mg, 8.58mmol, 60% 분산 오일)을 천천히 첨가하여 교반하였다. 이후 상기 혼합물은 상온에서 30분간 더 교반한 뒤, 건조된 디메틸포름아마이드에 용해된 4-플루오로-2-(트리플루오메틸)벤즈알데히드(1.2g, 7.8mmol) 용액을 10분 동안 첨가한 다음, 최초 물질들이 사라질 때까지 18시간 동안 상온에서 교반하였다. 이후 반응액에 얼음물을 첨가한 다음 에틸아세테이트 및 물로 추출하였다. 유기층은 물로 여러번 세척한 다음 무수황 마그네슘을 이용하여 건조시켰고, 여과 및 증발시켰다. 잔여 오일은 실리카 겔 컬럼크로마토그래피를 수행하였으며, 이때 용출용매로 헥산 및 에틸아세테이트가 20:1로 혼합된 용매를 사용하였다. 그 결과, 4-(2-시클로헥실에톡시)-2-(트리플루오로메틸)벤즈알데히드(1.77g, 75.6% 수율)의 중간체를 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-시클로헥실에톡시)-2-(트리플루오로메틸)벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylethoxy)-2-(trifluromethyl)benzylidene)thiazolidine-2,4-dione)(1.06 g, 79.7% 수율)을 수득하였다. 상기 수득한 유도체 81 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.731 (s, 1H), 7.778 (s, 1H), 7.689 (d, J = 9.0 Hz, 1H), 7.407(d, J = 9.0Hz, 1H), 7.371 (s, 1H), 4.168 (t, J = 12.9 Hz, 2H), 1.598-1.750(m, 7H), 1.455-1.598 (m, 1H), 1.099-1.265 (m, 3H),0.884-0.994 (m, 2H)이었다.To a solution of cyclohexaneethanol (1 g, 7.8 mmol) dissolved in dried dimethylformamide (30 ml) was slowly added sodium hydride (343.2 mg, 8.58 mmol, 60% dispersion oil) under nitrogen at room temperature and stirred. After the mixture was further stirred at room temperature for 30 minutes, 4-fluoro-2- (trifluoromethyl) benzaldehyde (1.2 g, 7.8 mmol) solution dissolved in dried dimethylformamide was added for 10 minutes. Stir at room temperature for 18 hours until the initial materials disappeared. After the addition of ice water to the reaction solution and extracted with ethyl acetate and water. The organic layer was washed several times with water and then dried over anhydrous magnesium, filtered and evaporated. The remaining oil was subjected to silica gel column chromatography, and a solvent in which hexane and ethyl acetate were mixed at 20: 1 was used as an elution solvent. As a result, an intermediate of 4- (2-cyclohexylethoxy) -2- (trifluoromethyl) benzaldehyde (1.77 g, 75.6% yield) was obtained, and the obtained intermediate product was then obtained as a derivative of Example 51. A 5- (4- (2-cyclohexylethoxy) represented by the above formula was carried out in the same manner, except that it was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the preparation process. 2- (trifluoromethyl) benzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylethoxy) -2- (trifluromethyl) benzylidene) thiazolidine-2,4-dione) (1.06 g, 79.7% yield). The obtained derivative 81 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.731 (s, 1H), 7.778 (s, 1H), 7.689 (d, J = 9.0 Hz, 1H), 7.407 (d , J = 9.0 Hz, 1H), 7.371 (s, 1H), 4.168 (t, J = 12.9 Hz, 2H), 1.598-1.750 (m, 7H), 1.455-1.598 (m, 1H), 1.099-1.265 ( m, 3H), 0.884-0.994 (m, 2H).
<실시예 82><Example 82>
본 발명에 따른 유도체 82의 제조Preparation of the derivative 82 according to the invention
하기 화학식으로 나타내는 유도체 82를 다음과 같은 방법으로 제조하였다.      Derivative 82 represented by the following formula was prepared in the following manner.
<유도체 82의 화학식>      <Formula of derivative 82>
Figure PCTKR2009007995-appb-I000087
Figure PCTKR2009007995-appb-I000087
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-시클로헥실-1-부탄올(1g, 6.4mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시-3-니트로벤즈알데히드(1.07g, 6.4mmol)를 사용하며, 트리페닐포스피린을 1.85g, 7.04mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-시클로헥실부톡시)-3-니트로벤즈알데히드 1.32g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 81%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(2-시클로헥실부톡시)-3-니트로벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylbutoxy)-3-nitrobenzylidene) thiazolidine-2,4-dione)(1.23g, 77.8% 수율)을 수득하였다. 상기 수득한 유도체 82 화합물은 1H NMR (300 MHz, DMSO-d 6) δ8.134 (s, 1H), 7.847 (d, J =9.0 Hz, 2H), 7.787 (s, 1H), 7.527(d, J = 9.0 Hz, 2H), 4.225 (t, J =12.3 Hz, 2H), 1.625-1.751 (m, 7H), 1.419-1.467 (m, 2H), 1.079-1.220 (m, 6H), 0.831-0.896 (m, 2H)이었다.In preparing the derivative of Example 51, 4-cyclohexyl-1-butanol (1 g, 6.4 mmol) was used instead of cyclohexanemethanol, and 4-hydroxy-3- instead of 4-hydroxy-3-methylbenzaldehyde. Nitrobenzaldehyde (1.07 g, 6.4 mmol) was used, and the intermediate product 4- (2-cyclohexylbutoxy)-was used in the same manner except that triphenylphosphine was used in an amount of 1.85 g and 7.04 mmol. 1.32 g of 3-nitrobenzaldehyde were obtained, wherein the yield of the intermediate product was 81%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4- (2-cyclohexylbutoxy) -3-nitrobenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylbutoxy) -3-nitrobenzylidene) thiazolidine-2, 4-dione) (1.23 g, 77.8% yield) was obtained. The obtained derivative 82 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ8.134 (s, 1H), 7.847 (d, J = 9.0 Hz, 2H), 7.787 (s, 1H), 7.527 (d , J = 9.0 Hz, 2H), 4.225 (t, J = 12.3 Hz, 2H), 1.625-1.751 (m, 7H), 1.419-1.467 (m, 2H), 1.079-1.220 (m, 6H), 0.831- 0.896 (m, 2H).
<실시예 83><Example 83>
본 발명에 따른 유도체 83의 제조Preparation of the derivative 83 according to the present invention
하기 화학식으로 나타내는 유도체 83을 다음과 같은 방법으로 제조하였다.      Derivative 83 represented by the following formula was prepared in the following manner.
<유도체 83의 화학식>      <Formula of derivative 83>
Figure PCTKR2009007995-appb-I000088
Figure PCTKR2009007995-appb-I000088
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산에탄올(1g, 7.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 5-히드록시-2-니트로벤즈알데히드(1.30g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 5-(2-시클로헥실에톡시)-2-니트로벤즈알데히드 1.68g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 77.8%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(5-(2-시클로헥실에톡시)-2-니트로벤질리덴)티아졸리딘-2,4-디온(5-(5-(2-cyclohexylethoxy)-2-nitrobenzylidene)thiazolidine-2,4-dione)(1.24 g, 87% 수율)을 수득하였다. 상기 수득한 유도체 83 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.644 (s, 1H), 8.003 (d, J = 8.4 Hz, 1H), 7.799 (s, 1H), 7.611 (s, 1H), 7.273 (s, J = 8.4 Hz, 1H), 4.255 (t, J = 13.5 Hz, 2H), 1.618-1.746 (m, 7H), 1.401-1.546 (m, 1H), 1.144-1.323 (m, 3H), 0.928-0.1.006 (m, 2H)이었다.In preparing the derivative of Example 51, cyclohexaneethanol (1 g, 7.8 mmol) was used instead of cyclohexane methanol, and 5-hydroxy-2-nitrobenzaldehyde (1.30 g) instead of 4-hydroxy-3-methylbenzaldehyde. , 7.8 mmol) and the intermediate product 5- (2-cyclohexylethoxy) -2-nitrobenzaldehyde 1.68 using the same method except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. g was obtained, wherein the yield of the intermediate product was 77.8%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (5- (2-cyclohexylethoxy) -2-nitrobenzylidene) thiazolidine-2,4-dione (5- (5- (2-cyclohexylethoxy) -2-nitrobenzylidene) thiazolidine-2, 4-dione) (1.24 g, 87% yield) was obtained. The obtained derivative 83 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.644 (s, 1H), 8.003 (d, J = 8.4 Hz, 1H), 7.799 (s, 1H), 7.611 (s , 1H), 7.273 (s, J = 8.4 Hz, 1H), 4.255 (t, J = 13.5 Hz, 2H), 1.618-1.746 (m, 7H), 1.401-1.546 (m, 1H), 1.144-1.323 ( m, 3H), 0.928-0.1.006 (m, 2H).
<실시예 84><Example 84>
본 발명에 따른 유도체 84의 제조Preparation of Derivative 84 According to the Invention
하기 화학식으로 나타내는 유도체 84를 다음과 같은 방법으로 제조하였다.      Derivative 84 represented by the following formula was prepared in the following manner.
<유도체 84의 화학식>      <Formula of derivative 84>
Figure PCTKR2009007995-appb-I000089
Figure PCTKR2009007995-appb-I000089
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 3-시클로헥실-1-프로판올(1g, 7.0mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시-3-메톡시벤즈알데히드(1.07g, 7.0mmol)를 사용하며, 트리페닐포스피린을 2.02g, 7.7mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-시클로헥실프로폭시)-3-메톡시벤즈알데히드 1.64g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 84.5%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-4-(2-시클로헥실프로폭시)-3-메톡시벤질리덴)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylpropoxy)-3- methoxybenzylidene)thiazolidine-2,4-dione) (1.13 g, 83.1% 수율)을 수득하였다. 상기 수득한 유도체 84 화합물은 1H NMR (300 MHz, DMSO-d 6) δ8.219 (s, 1H), 7.694 (s, 1H), 7.014 (d, J = 10.2 Hz, 2H), 6.893(d, J = 10.2 Hz, 2H), 6.764 (s, 1H), 4.123 (t, J = 14.4 Hz, 2H), 3.787 (s, 3H), 1.725 (t, J = 14.4 Hz, 2H), 1.444-1.563 (m, 4H), 1.102-1.224 (m, 6H), 0.796-1.103 (m, 3H)이었다.In preparing the derivative of Example 51, 3-cyclohexyl-1-propanol (1 g, 7.0 mmol) was used instead of cyclohexanemethanol, and 4-hydroxy-3- instead of 4-hydroxy-3-methylbenzaldehyde. Methoxybenzaldehyde (1.07 g, 7.0 mmol) was used, and the intermediate product 4- (2-cyclohexylpropoxy) was obtained using the same method except that triphenylphosphine was used in an amount of 2.02 g, 7.7 mmol. 1.64 g of 3-methoxybenzaldehyde were obtained with a yield of 84.5% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5-4- (2-cyclohexylpropoxy) -3-methoxybenzylidene) thiazolidine-2,4-dione (5- (4- (2-cyclohexylpropoxy) -3-methoxybenzylidene) thiazolidine-2,4 -dione) (1.13 g, 83.1% yield) was obtained. The obtained derivative 84 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.219 (s, 1H), 7.694 (s, 1H), 7.014 (d, J = 10.2 Hz, 2H), 6.893 (d , J = 10.2 Hz, 2H), 6.764 (s, 1H), 4.123 (t, J = 14.4 Hz, 2H), 3.787 (s, 3H), 1.725 (t, J = 14.4 Hz, 2H), 1.444-1.563 (m, 4H), 1.102-1.224 (m, 6H) and 0.796-1.103 (m, 3H).
<실시예 85><Example 85>
본 발명에 따른 유도체 85의 제조Preparation of Derivative 85 According to the Invention
하기 화학식으로 나타내는 유도체 85를 다음과 같은 방법으로 제조하였다.      Derivative 85 represented by the following formula was prepared in the following manner.
<유도체 85의 화학식>      <Formula of derivative 85>
Figure PCTKR2009007995-appb-I000090
Figure PCTKR2009007995-appb-I000090
건조된 디메틸포름아마이드(30ml)에 용해된 벤질알콜(1g, 9.2mmol) 용액에 상온의 질소 조건 하에서 수소화 나트륨(404.8mg, 10.12mmol, 60% 분산 오일)을 천천히 첨가하여 교반하였다. 이후 상기 혼합물은 상온에서 30분간 더 교반한 뒤, 건조된 디메틸포름아마이드에 용해된 4-플루오로-2-클로로벤즈알데히드(1.46g, 9.2mmol) 용액을 10분 동안 첨가한 다음, 최초 물질들이 사라질 때까지 18시간 동안 상온에서 교반하였다. 이후 반응액에 얼음물을 첨가한 다음 에틸아세테이트 및 물로 추출하였다. 유기층은 물로 여러번 세척한 다음 무수황 마그네슘을 이용하여 건조시켰고, 여과 및 증발시켰다. 잔여 오일은 실리카 겔 컬럼 크로마토그래피를 수행하였으며, 이때 용출용매로 헥산 및 에틸아세테이트가 20:1로 혼합된 용매를 사용하였다. 그 결과, 4-(벤질옥시)-2-클로로벤즈알데히드(1.64g, 71.9% 수율)의 중간체를 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-(벤질옥시)-2-클로로벤질리덴)티아졸리딘-2,4-디온(5-(4-(benzyloxy)-2-chlorobenzylidene)thiazolidine-2,4-dione)(0.98 g, 70.1% 수율)을 수득하였다. 상기 수득한 유도체 85 화합물은 1H NMR (300 MHz, DMSO-d 6) δ7.850 (s, 1H), 7.561 (d, J = 9.9 Hz, 1H), 7.332-7.499 (m, 6H ), 7.221 (d, J = 9.9 Hz, 1H), 5.224 (s, 2H)이었다.To a benzyl alcohol (1 g, 9.2 mmol) dissolved in dried dimethylformamide (30 ml) was slowly added sodium hydride (404.8 mg, 10.12 mmol, 60% dispersion oil) under nitrogen at room temperature and stirred. After further stirring the mixture for 30 minutes at room temperature, the solution of 4-fluoro-2-chlorobenzaldehyde (1.46g, 9.2mmol) dissolved in dried dimethylformamide for 10 minutes, and then the first substances disappear Stir at room temperature for 18 hours. After the addition of ice water to the reaction solution and extracted with ethyl acetate and water. The organic layer was washed several times with water and then dried over anhydrous magnesium, filtered and evaporated. The remaining oil was subjected to silica gel column chromatography, in which a solvent in which hexane and ethyl acetate were mixed at 20: 1 was used as the elution solvent. As a result, an intermediate of 4- (benzyloxy) -2-chlorobenzaldehyde (1.64 g, 71.9% yield) was obtained, and the obtained intermediate product was then obtained in the second step of the preparation of the derivative of Example 51 above. 5- (4- (benzyloxy) -2-chlorobenzylidene) thiazolidine-2 represented by the above formula by the same method except that it was used instead of (2-cyclomethoxy) -3-methylbenzaldehyde, 4-dione (5- (4- (benzyloxy) -2-chlorobenzylidene) thiazolidine-2,4-dione) (0.98 g, 70.1% yield) was obtained. The obtained derivative 85 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.850 (s, 1H), 7.561 (d, J = 9.9 Hz, 1H), 7.332-7.499 (m, 6H), 7.221 (d, J = 9.9 Hz, 1H), 5.224 (s, 2H).
<실시예 86><Example 86>
본 발명에 따른 유도체 86의 제조Preparation of Derivatives 86 According to the Invention
하기 화학식으로 나타내는 유도체 86을 다음과 같은 방법으로 제조하였다.      Derivative 86 represented by the following formula was prepared in the following manner.
<유도체 86의 화학식>      <Formula of derivative 86>
Figure PCTKR2009007995-appb-I000091
Figure PCTKR2009007995-appb-I000091
상기 실시예 85의 방법에서 벤질알콜(1g, 9.2mmol) 용액 대신 2-페닐에탄올(1g, 8.2mmol)용액을 사용한 것을 제외하고는 동일한 방법을 수행하여, 중간체 산물인 2-클로로-4-페닐에톡시벤즈알데히드 1.64g(77% 수율)을 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-페닐에톡시벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione)(0.96 g, 69.6% 수율)을 수득하였다. 상기 수득한 유도체 86 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.645 (s, 1H), 7.863 (s, 1H), 7.500 (d, J = 7.8 Hz, 1H ), 7.188-7.274 ( m, 6H), 7.127 (d, J = 7.8 Hz, 1H), 4.323 (t, J= 13.5 Hz, 2H), 3.064 (t, J = 13.8 Hz, 2H)이었다. The procedure of Example 85 was repeated except that 2-phenylethanol (1 g, 8.2 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution, and 2-chloro-4-phenyl as an intermediate product. 1.64 g (77% yield) of ethoxybenzaldehyde were obtained, and the obtained intermediate product was then used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative preparation of Example 51. The same procedure was followed except that 5- (2-chloro-4-phenylethoxybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-4-phenylethoxybenzylidene) represented by the above formula. thiazolidine-2,4-dione) (0.96 g, 69.6% yield) was obtained. The obtained derivative 86 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.645 (s, 1H), 7.863 (s, 1H), 7.500 (d, J = 7.8 Hz, 1H), 7.188-7.274 (m, 6H), 7.127 (d, J = 7.8 Hz, 1H), 4.323 (t, J = 13.5 Hz, 2H), 3.064 (t, J = 13.8 Hz, 2H).
<실시예 87><Example 87>
본 발명에 따른 유도체 87의 제조Preparation of Derivative 87 According to the Invention
하기 화학식으로 나타내는 유도체 87을 다음과 같은 방법으로 제조하였다.      Derivative 87 represented by the following formula was prepared in the following manner.
<유도체 87의 화학식>      <Formula of derivative 87>
Figure PCTKR2009007995-appb-I000092
Figure PCTKR2009007995-appb-I000092
상기 실시예 85의 방법에서 벤질알콜(1g, 9.2mmol) 용액 대신 3-페닐-1-프로판올(1g, 7.3mmol)용액을 사용한 것을 제외하고는 동일한 방법을 수행하여, 중간체 산물인 2-클로로-4-페닐프로폭시벤즈알데히드 1.4g(69.7% 수율)을 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-페닐프로폭시벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-4-phenylpropoxybenzylidene)thiazolidine-2,4-dione)(1.0 g, 72.7% 수율)을 수득하였다. 상기 수득한 유도체 87 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.548 (s, 1H), 7.924 (s, 1H), 7.482 (d, J = 7.8 Hz, 1H ), 7.200-7.368( m, 6H), 7.212 (d, J = 7.8 Hz, 1H), 4.139 (t, J = 13.5 Hz, 2H), 3.156 (t, J = 13.8 Hz, 2H), 2.591-2.622 (m, 2H)이었다.The procedure of Example 85 was repeated except that 3-phenyl-1-propanol (1 g, 7.3 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution. The intermediate product 2-chloro- 1.4 g (69.7% yield) of 4-phenylpropoxybenzaldehyde were obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethoxy) -3-methyl in the second step of the preparation of the derivative of Example 51. A 5- (2-chloro-4-phenylpropoxybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-4) represented by the above formula was subjected to the same method except that it was used instead of benzaldehyde. -phenylpropoxybenzylidene) thiazolidine-2,4-dione) (1.0 g, 72.7% yield) was obtained. The obtained derivative 87 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.548 (s, 1H), 7.924 (s, 1H), 7.482 (d, J = 7.8 Hz, 1H), 7.200-7.368 (m, 6H), 7.212 (d, J = 7.8 Hz, 1H), 4.139 (t, J = 13.5 Hz, 2H), 3.156 (t, J = 13.8 Hz, 2H), 2.591-2.622 (m, 2H) It was.
<실시예 88><Example 88>
본 발명에 따른 유도체 88의 제조Preparation of the derivative 88 according to the invention
하기 화학식으로 나타내는 유도체 88을 다음과 같은 방법으로 제조하였다.      Derivative 88 represented by the following formula was prepared in the following manner.
<유도체 88의 화학식>      <Formula of derivative 88>
Figure PCTKR2009007995-appb-I000093
Figure PCTKR2009007995-appb-I000093
상기 실시예 85의 방법에서 벤질알콜(1g, 9.2mmol) 용액 대신 4-페닐-1-부탄올(1g, 6.7mmol) 용액을 사용한 것을 제외하고는 동일한 방법을 수행하여, 중간체 산물인 2-클로로-4-페닐부톡시벤즈알데히드 1.39g(72.4% 수율)을 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-페닐부턱시벤질리덴)티아졸리딘-2,4-디온( 5-(2-chloro-4-phenbutoxybenzylidene)thiazolidine-2,4-dione) (0.98 g, 73.1% 수율)을 수득하였다. 상기 수득한 유도체 88 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.64 (s, 1H), 7.81 (s, 1H), 7.511 (d, J = 9.3 Hz, 1H ), 7.161-7.296( m, 6H), 7.105 (d, J = 9.3 Hz, 1H), 4.084 (t, J = 12.9 Hz, 2H), 2.654 (t, J = 13.8 Hz, 2H), 1.653-1.724 (m, 4H)이었다.The procedure of Example 85 was repeated except that 4-phenyl-1-butanol (1 g, 6.7 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution. The intermediate product 2-chloro- 1.39 g (72.4% yield) of 4-phenylbutoxybenzaldehyde were obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethoxy) -3-methyl in the second step of the preparation of the derivative of Example 51. A 5- (2-chloro-4-phenylbutybenzylidene) thiazolidine-2,4-dione (5- (2-chloro-4) represented by the above formula was subjected to the same method except that it was used instead of benzaldehyde. -phenbutoxybenzylidene) thiazolidine-2,4-dione) (0.98 g, 73.1% yield) was obtained. The obtained derivative 88 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.64 (s, 1H), 7.81 (s, 1H), 7.511 (d, J = 9.3 Hz, 1H), 7.161-7.296 (m, 6H), 7.105 (d, J = 9.3 Hz, 1H), 4.084 (t, J = 12.9 Hz, 2H), 2.654 (t, J = 13.8 Hz, 2H), 1.653-1.724 (m, 4H) It was.
<실시예 89><Example 89>
본 발명에 따른 유도체 89의 제조Preparation of the derivative 89 according to the invention
하기 화학식으로 나타내는 유도체 89를 다음과 같은 방법으로 제조하였다.      Derivative 89 represented by the following formula was prepared in the following manner.
<유도체 89의 화학식>      <Formula of derivative 89>
Figure PCTKR2009007995-appb-I000094
Figure PCTKR2009007995-appb-I000094
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-(2-히드로퍼옥시프로필-1-메틸시클로헥스-1-엔(1g, 6.5mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시벤즈알데히드(0.79g, 6.5mmol)를 사용하며, 트리페닐포스피린을 1.85g, 7.05mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-(2-(4-메틸시클로헥스-3-엔-1-일)프로폭시)벤즈알데히드 1.42g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 78.0%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{4-[2-(4-메틸시클로헥스-3-엔-1-일)프로폭시]벤질리덴-2,4-디온(5-{4-[2-(4-methylcyclohex-3-en-1-yl)propoxy]benzylidene}-1,3-thiazolidine-2,4-dione)(1.23 g, 89.8% 수율)을 수득하였다. 상기 수득한 유도체 89 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.496 (s, 1H), 7.726 (s, 1H), 7.547 (d, J = 9.0 Hz, 2H ), 7.106 (d, J = 9.0 Hz, 2H), 5.344 (s, 1H), 3.991-4.042 (m, 1H), 3.844-3.898 (m, 1H), 1.085-2.069 (m, 7H), 1.711 (s, 3H), 1.347-1.637 (m, 2H), 1.257 (t, J = 13.8 Hz, 3H), 0.860-0.882 (m, 1H)이었다.In preparing the derivative of Example 51, 4- (2-hydroperoxypropyl-1-methylcyclohex-1-ene (1 g, 6.5 mmol) was used instead of cyclohexanemethanol, and 4-hydroxy-3 4-hydroxybenzaldehyde (0.79 g, 6.5 mmol) is used instead of methylbenzaldehyde, and the intermediate product 4- (2 is used in the same manner except that triphenylphosphine is used in an amount of 1.85 g and 7.05 mmol. 1.42 g of-(4-methylcyclohex-3-en-1-yl) propoxy) benzaldehyde was obtained, wherein the yield of the intermediate product was 78.0% .The obtained intermediate product was then obtained as a derivative of Example 51. Except for using instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the preparation process, the same procedure was followed to obtain 5- {4- [2- (4-methylcyclo) Hex-3-en-1-yl) propoxy] benzylidene-2,4-dione (5- {4- [2- (4-methylcyclohex-3 -en-1-yl) propoxy] benzylidene} -1,3-thiazolidine-2,4-dione) (1.23 g, 89.8% yield) The obtained derivative 89 compound was subjected to 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.496 (s, 1H), 7.726 (s, 1H), 7.547 (d, J = 9.0 Hz, 2H), 7.106 (d, J = 9.0 Hz, 2H), 5.344 (s, 1H ), 3.991-4.042 (m, 1H), 3.844-3.898 (m, 1H), 1.085-2.069 (m, 7H), 1.711 (s, 3H), 1.347-1.637 (m, 2H), 1.257 (t, J = 13.8 Hz, 3H), 0.860-0.882 (m, 1H).
<실시예 90><Example 90>
본 발명에 따른 유도체 90의 제조Preparation of Derivative 90 According to the Invention
하기 화학식으로 나타내는 유도체 90을 다음과 같은 방법으로 제조하였다.     Derivative 90 represented by the following formula was prepared in the following manner.
<유도체 90의 화학식>      <Formula of derivative 90>
Figure PCTKR2009007995-appb-I000095
Figure PCTKR2009007995-appb-I000095
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-(2-히드록시에틸)티오모르폴린 1,1-디옥시드(1g, 5.6mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-니트로-4-히드록시벤즈알데히드(936mg, 5.6mmol)를 사용하며, 트리페닐포스피린을 1.62g, 6.2mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-니트로-4-(2-티오모르폴린1,1-디옥시드에톡시)벤즈알데히드 1.45g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 79.2%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[3-니트로-4-(2-티오모르폴린1,1-디옥시드에톡시)벤질리덴]-2,4-티아졸리딘 디온(5-[3-nitro-4-(2-Thiomorpholine1,1-Dioxideethoxy)benzylidene]-2,4-thiazolidine dione) (0.88 g, 67.7% 수율)을 수득하였다. 상기 수득한 유도체 90 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.630 (s, 1H), 8.148 (s, 1H), 7.860 (d, J = 10.8 Hz, 1H), 7.560 (d, J= 10.8 Hz, 1H), 7.782 (s, 1H), 4.360 (t, J = 11.1 Hz, 2H), 3.043-3.119 (m, 8H), 2.976 (t, J = 11.1 Hz, 2H)이었다.4- (2-hydroxyethyl) thiomorpholine 1,1-dioxide (1 g, 5.6 mmol) was used instead of cyclohexanemethanol in the preparation of the derivative of Example 51, and 4-hydroxy-3- 3-nitro-4-hydroxybenzaldehyde (936 mg, 5.6 mmol) was used instead of methyl benzaldehyde, and the intermediate product 3- was used in the same manner except that triphenylphosphine was used in an amount of 1.62 g and 6.2 mmol. 1.45 g of nitro-4- (2-thiomorpholine 1,2-dioxideethoxy) benzaldehyde were obtained, with a yield of 79.2% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- [3-nitro-4- (2-thiomorpholine 1,1-dioxideethoxy) benzylidene] -2,4-thiazolidine dione (5- [3-nitro-4- (2-Thiomorpholine1 , 1-Dioxideethoxy) benzylidene] -2,4-thiazolidine dione) (0.88 g, 67.7% yield) was obtained. The obtained derivative 90 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.630 (s, 1H), 8.148 (s, 1H), 7.860 (d, J = 10.8 Hz, 1H), 7.560 (d , J = 10.8 Hz, 1H), 7.782 (s, 1H), 4.360 (t, J = 11.1 Hz, 2H), 3.043-3.119 (m, 8H), 2.976 (t, J = 11.1 Hz, 2H).
<실시예 91><Example 91>
본 발명에 따른 유도체 91의 제조Preparation of the derivative 91 according to the invention
하기 화학식으로 나타내는 유도체 91을 다음과 같은 방법으로 제조하였다.     Derivative 91 represented by the following formula was prepared in the following manner.
<유도체 91의 화학식>      <Formula of derivative 91>
Figure PCTKR2009007995-appb-I000096
Figure PCTKR2009007995-appb-I000096
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-메틸-1-시클로헥산메탄올(1g, 5.6mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.22g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-[(4-메틸시클로헥실)메톡시]벤즈알데히드 1.49g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 74.1%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{2-클로로-3-[(4-메틸시클로헥실)메톡시]벤질리덴}-1,3-티아졸리딘-2,4-디온(5-{2-chloro-3-[(4-methylcyclohexyl)methoxy]benzylidene}-1,3-thiazolidine-2,4-dione)(1.12 g, 81.2% 수율)을 수득하였다. 상기 수득한 유도체 91 화합물은 1H NMR (300 MHz, DMSO-d 6)) δ8.242 (s, 1H), 7.262 (m, 1H), 7.111 (d, J = 9.3 Hz, 1H), 7.025 (d, J = 9.3 Hz, 1H), 3.961 (d, J = 7.2 Hz, 2H), 2.038-2.076 (m, 1H), 1.456-1.810 (m, 5H), 1.233-1.339 (m, 2H), 0.954 (d, J = 6.9 Hz, 1H), 0.900-1.416 (m, 2H)이었다. In preparing the derivative of Example 51, 4-methyl-1-cyclohexanemethanol (1 g, 5.6 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3- instead of 4-hydroxy-3-methylbenzaldehyde. Hydroxybenzaldehyde (1.22 g, 7.8 mmol) was used, and the intermediate product 2-chloro-3-[(4- was used in the same manner except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.49 g of methylcyclohexyl) methoxy] benzaldehyde was obtained, wherein the yield of the intermediate product was 74.1%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- {2-chloro-3-[(4-methylcyclohexyl) methoxy] benzylidene} -1,3-thiazolidine-2,4-dione (5- {2-chloro-3-[(4 -methylcyclohexyl) methoxy] benzylidene} -1,3-thiazolidine-2,4-dione) (1.12 g, 81.2% yield) was obtained. The obtained derivative 91 compound is 1 H NMR (300 MHz, DMSO- d 6 )) δ 8.242 (s, 1H), 7.262 (m, 1H), 7.111 (d, J = 9.3 Hz, 1H), 7.025 ( d, J = 9.3 Hz, 1H), 3.961 (d, J = 7.2 Hz, 2H), 2.038-2.076 (m, 1H), 1.456-1.810 (m, 5H), 1.233-1.339 (m, 2H), 0.954 (d, J = 6.9 Hz, 1H), 0.900-1.416 (m, 2H).
<실시예 92><Example 92>
본 발명에 따른 유도체 92의 제조Preparation of the derivative 92 according to the invention
하기 화학식으로 나타내는 유도체 92를 다음과 같은 방법으로 제조하였다.     Derivative 92 represented by the following formula was prepared in the following manner.
<유도체 92의 화학식>      <Formula of derivative 92>
Figure PCTKR2009007995-appb-I000097
Figure PCTKR2009007995-appb-I000097
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-이소프로폭시에탄올(1g, 9.6mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.50g, 9.6mmol)를 사용하며, 트리페닐포스피린을 2.77g, 10.56mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-[2-(프로판-2-일옥시)에톡시]벤즈알데히드 1.46g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 62.6%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{2-클로로-3-[2-(프로판-2-일옥시)에톡시]벤질리덴}-1,3-티아졸리딘-2,4-디온(5-{2-chloro-3-[2-(propan-2-yloxy)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione) (1.06 g, 75.7% 수율)을 수득하였다. 상기 수득한 유도체 92 화합물은 1H NMR (300 MHz, CDCl3) δ8.623 (s, 1H), 8.208 (s, 1H), 7.263 (m, 1H), 7.111 (d, J =7.8 Hz, 1H), 7.055 (d, J = 8.7 Hz, 1H), 4.223 (t, J = 10.2Hz, 2H), 3.880 (t, J = 10.2 Hz, 2H), 3.753 (m, 1H), 1.230 (d, J = 5.7 Hz, 6H)이었다.In the preparation of the derivative of Example 51, 2-isopropoxyethanol (1 g, 9.6 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxybenzaldehyde instead of 4-hydroxy-3-methylbenzaldehyde. (1.50 g, 9.6 mmol), and the intermediate product 2-chloro-3- [2- (propane-2) using the same method except that triphenylphosphine was used in an amount of 2.77 g and 10.56 mmol. 1.46 g of -yloxy) ethoxy] benzaldehyde were obtained, with a yield of 62.6% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- {2-chloro-3- [2- (propan-2-yloxy) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione (5- {2-chloro-3- [2- (propan-2-yloxy) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione) (1.06 g, 75.7% yield) was obtained. The obtained derivative 92 compound is 1 H NMR (300 MHz, CDCl 3 ) δ 8.623 (s, 1H), 8.208 (s, 1H), 7.263 (m, 1H), 7.111 (d, J = 7.8 Hz, 1H ), 7.055 (d, J = 8.7 Hz, 1H), 4.223 (t, J = 10.2Hz, 2H), 3.880 (t, J = 10.2 Hz, 2H), 3.753 (m, 1H), 1.230 (d, J = 5.7 Hz, 6H).
<실시예 93><Example 93>
본 발명에 따른 유도체 93의 제조Preparation of Derivative 93 According to the Invention
하기 화학식으로 나타내는 유도체 93을 다음과 같은 방법으로 제조하였다.     Derivative 93 represented by the following formula was prepared in the following manner.
<유도체 93의 화학식>      <Formula of derivative 93>
Figure PCTKR2009007995-appb-I000098
Figure PCTKR2009007995-appb-I000098
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-피리딘에탄올(1g, 8.1mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.27g, 8.1mmol)를 사용하며, 트리페닐포스피린을 2.33g, 8.9mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-[2-(피리딘-2-일)에톡시]벤즈알데히드 1.74g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 82.1%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{2-클로로-3-[2-(피리딘-2-일)에톡시]벤질리덴}-1,3-티아졸리딘-2,4-디온(5-{2-chloro-3-[2-(pyridin-2-yl)ethoxy]benzylidene} -1,3-thiazolidine-2,4-dione) (1.11 g, 80.4% 수율)을 수득하였다. 상기 수득한 유도체 93 화합물은 1H NMR (300 MHz, CDCl3 ) δ8.558 (s, J = 3.9 Hz, 1H), 8.203 (s, 1H), 7.659 (t, J = 7.8 Hz, 1H),7.151-7.210 (m, 3H), 7.113 (d, J = 8.1 Hz, 2H), 4.199 (t, J= 14.7 Hz, 2H), 3.199 (t, J = 14.7 Hz, 2H)이었다.In the preparation of the derivative of Example 51, 2-pyridineethanol (1 g, 8.1 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxybenzaldehyde (1.27) instead of 4-hydroxy-3-methylbenzaldehyde. g, 8.1 mmol) and the intermediate product 2-chloro-3- [2- (pyridin-2-yl) using the same method except that triphenylphosphine was used in an amount of 2.33 g and 8.9 mmol. 1.74 g)) ethoxy] benzaldehyde was obtained, with a yield of 82.1% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- {2-chloro-3- [2- (pyridin-2-yl) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione (5- {2-chloro-3- [ 2- (pyridin-2-yl) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione) (1.11 g, 80.4% yield) was obtained. The obtained derivative 93 compound is 1 H NMR (300 MHz, CDCl 3 ) δ 8.558 (s, J = 3.9 Hz, 1H), 8.203 (s, 1H), 7.659 (t, J = 7.8 Hz, 1H), 7.151-7.210 (m, 3H), 7.113 (d, J = 8.1 Hz, 2H), 4.199 (t, J = 14.7 Hz, 2H), 3.199 (t, J = 14.7 Hz, 2H).
<실시예 94><Example 94>
본 발명에 따른 유도체 94의 제조Preparation of the derivative 94 according to the invention
하기 화학식으로 나타내는 유도체 94를 다음과 같은 방법으로 제조하였다.     Derivative 94 represented by the following formula was prepared in the following manner.
<유도체 94의 화학식>      <Formula of derivative 94>
Figure PCTKR2009007995-appb-I000099
Figure PCTKR2009007995-appb-I000099
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-이소프로폭시에탄올(1g, 9.6mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.50g, 9.6mmol)를 사용하며, 트리페닐포스피린을 2.77g, 10.56mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-[2-(프로판-2-일옥시)에톡시]벤즈알데히드 1.54g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 71.5%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{3-클로로-4-[2-(프로판-2-일옥시)에톡시]벤질리덴}-1,3-티아졸리딘-2,4-디온(5-{3-chloro-4-[2-(propan-2-yloxy)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione)(1.09 g, 77.3% 수율)을 수득하였다. 상기 수득한 유도체 94 화합물은 1H NMR (300 MHz, CDCl3 ) δ7.607 (s, 1H), 7.507 (s, 1H), 7.373 (d, J = 8.4 Hz, 1H), 7.052 (d, J = 8.4 Hz, 1H), 4.255 (t, J = 10.2Hz, 2H), 3.881 (t, J = 10.2 Hz, 2H), 1.216 (d, J = 3.9 Hz, 6H)이었다.In the preparation of the derivative of Example 51, 2-isopropoxyethanol (1 g, 9.6 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxy-3-methylbenzaldehyde. (1.50 g, 9.6 mmol) and the intermediate product 3-chloro-4- [2- (propane-2) using the same method except that triphenylphosphine was used in an amount of 2.77 g and 10.56 mmol. 1.54 g of -yloxy) ethoxy] benzaldehyde was obtained, wherein the yield of the intermediate product was 71.5%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- {3-chloro-4- [2- (propan-2-yloxy) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione (5- {3-chloro-4- [2- (propan-2-yloxy) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione) (1.09 g, 77.3% yield) was obtained. The obtained derivative 94 compound was 1 H NMR (300 MHz, CDCl 3 ) δ7.607 (s, 1H), 7.507 (s, 1H), 7.373 (d, J = 8.4 Hz, 1H), 7.052 (d, J = 8.4 Hz, 1H), 4.255 (t, J = 10.2 Hz, 2H), 3.881 (t, J = 10.2 Hz, 2H), 1.216 (d, J = 3.9 Hz, 6H).
<실시예 95><Example 95>
본 발명에 따른 유도체 95의 제조Preparation of the derivative 95 according to the invention
하기 화학식으로 나타내는 유도체 95를 다음과 같은 방법으로 제조하였다.      Derivative 95 represented by the following formula was prepared in the following manner.
<유도체 95의 화학식>      <Formula of derivative 95>
Figure PCTKR2009007995-appb-I000100
Figure PCTKR2009007995-appb-I000100
상기 실시예 85의 방법에서 벤질알콜(1g, 9.2mmol) 용액 대신 시클로헥산올 (1g, 10mmol) 용액을 사용한 것을 제외하고는 동일한 방법을 수행하여, 중간체 산물인 2-클로로-4-(시클로헥실옥시)벤즈알데히드 1.74g(86% 수율)을 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-(시클로헥실옥시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-4-(cyclohexyloxy)benzylidene)thiazolidine-2,4-dione)(1.01 g, 71.1% 수율)을 수득하였다. 상기 수득한 유도체 95 화합물은 1H NMR (300 MHz, DMSO-d 6) δ10.581 (s, 1H), 7.658 (s, 1H), 7.529 (s, 1H), 7.398 (d, J = 8.4 Hz, 1H), 7.273 (d, J = 8.4 Hz, 1H), 1.451- 1.465 (m, 11H)이었다.The procedure of Example 85 was repeated except that the cyclohexanol (1 g, 10 mmol) solution was used instead of the benzyl alcohol (1 g, 9.2 mmol) solution. 1.74 g (86% yield) of siloxy) benzaldehyde was obtained, and the obtained intermediate product was then substituted for 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the second step of the derivative preparation of Example 51. The same procedure was followed except that 5- (2-chloro-4- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-) 4- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione) (1.01 g, 71.1% yield) was obtained. The obtained derivative 95 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 10.581 (s, 1H), 7.658 (s, 1H), 7.529 (s, 1H), 7.398 (d, J = 8.4 Hz , 1H), 7.273 (d, J = 8.4 Hz, 1H), 1.451-1.465 (m, 11H).
<실시예 96><Example 96>
본 발명에 따른 유도체 96의 제조Preparation of Derivative 96 According to the Invention
하기 화학식으로 나타내는 유도체 96을 다음과 같은 방법으로 제조하였다.      Derivative 96 represented by the following formula was prepared in the following manner.
<유도체 96의 화학식>      <Formula of derivative 96>
Figure PCTKR2009007995-appb-I000101
Figure PCTKR2009007995-appb-I000101
상기 실시예 85의 방법에서 벤질알콜(1g, 9.2mmol) 용액 대신 시클로헥산메탄올(1g, 9.2mmol) 용액을 사용한 것을 제외하고는 동일한 방법을 수행하여, 중간체 산물인 2-클로로-4-(3-시클로헥실메톡시)벤즈알데히드 1.67g(85% 수율)을 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-(3-시클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-4-(3-cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione)(1.05 g, 75.5% 수율)을 수득하였다. 상기 수득한 유도체 96 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.637 (s, 1H), 7.838 (s, 1H), 7.656 (d, J = 8.7 Hz, 1H), 7.223 (s, 1H), 7.110 (d, J = 8.7 Hz, 1H), 3.881 (d, J = 6.0 Hz, 2H), 1.641-1.797 (m, 6H), 1.194-1.263 (m, 3H), 1.002-1.039 (m, 2H)이었다. The procedure of Example 85 was repeated except that the solution of cyclohexanemethanol (1 g, 9.2 mmol) was used instead of the solution of benzyl alcohol (1 g, 9.2 mmol). The intermediate product 2-chloro-4- (3 1.67 g (85% yield) of -cyclohexylmethoxy) benzaldehyde was obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethoxy) -3- in the second step of the derivative preparation of Example 51. A 5- (2-chloro-4- (3-cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (5-) represented by the above formula was subjected to the same method except that it was used instead of methylbenzaldehyde. (2-chloro-4- (3-cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione) (1.05 g, 75.5% yield) was obtained. The obtained derivative 96 compoundOneH NMR (300 MHz, DMSO-d                 6) δ 12.637 (s, 1H), 7.838 (s, 1H), 7.656 (d,J = 8.7 Hz, 1H), 7.223 (s, 1H), 7.110 (d,J = 8.7 Hz, 1H), 3.881 (d,J = 6.0 Hz, 2H), 1.641-1.797 (m, 6H), 1.194-1.263 (m, 3H), 1.002-1.039 (m, 2H).
<실시예 97><Example 97>
본 발명에 따른 유도체 97의 제조Preparation of Derivatives 97 According to the Invention
하기 화학식으로 나타내는 유도체 97을 다음과 같은 방법으로 제조하였다.      Derivative 97 represented by the following formula was prepared in the following manner.
<유도체 97의 화학식>      <Formula of derivative 97>
Figure PCTKR2009007995-appb-I000102
Figure PCTKR2009007995-appb-I000102
상기 실시예 85의 방법에서 벤질알콜(1g, 9.2mmol) 용액 대신 3-시클로헥실-1-프로판올(1g, 7.0mmol) 용액을 사용한 것을 제외하고는 동일한 방법을 수행하여, 중간체 산물인 2-클로로-4-(3-시클로헥실프로폭시)벤즈알데히드 1.60g(81.2% 수율)을 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-(3-시클로헥실프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-4-(3-cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)(0.98 g, 72.6% 수율)을 수득하였다. 상기 수득한 유도체 97 화합물은 1H NMR (300 MHz, DMSO-d 6) δ7.785 (s, 1H), 7.439 (s, 1H), 7.654 (d, J= 11.7 Hz, 1H), 7.515 (d, J = 11.7 Hz, 1H), 3.014 ( t, J = 7.2 Hz, 2H), 1.135-1.642 ( m, 4H), 1.029-1.222 (m, 7H), 0.822 - 1.127 (m, 4H)이었다. The procedure of Example 85 was repeated except that 3-cyclohexyl-1-propanol (1 g, 7.0 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution. 1.60 g (81.2% yield) of 4- (3-cyclohexylpropoxy) benzaldehyde was obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethy in the second step in the preparation of the derivative of Example 51. 5- (2-Chloro-4- (3-cyclohexylpropoxy) benzylidene) thiazolidine-2,4 represented by the above formula by the same method except that it was used instead of -Dione (5- (2-chloro-4- (3-cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione) (0.98 g, 72.6% yield) was obtained. The obtained derivative 97 compound isOneH NMR (300 MHz, DMSO-d                 6) δ7.785 (s, 1H), 7.439 (s, 1H), 7.654 (d,J= 11.7 Hz, 1H), 7.515 (d,J = 11.7 Hz, 1H), 3.014 (t,J = 7.2 Hz, 2H), 1.135-1.642 (m, 4H), 1.029-1.222 (m, 7H), 0.822-1.127 (m, 4H).
<실시예 98>       <Example 98>
본 발명에 따른 유도체 98의 제조Preparation of Derivative 98 According to the Invention
하기 화학식으로 나타내는 유도체 98을 다음과 같은 방법으로 제조하였다.      Derivative 98 represented by the following formula was prepared in the following manner.
<유도체 98의 화학식>      <Formula of derivative 98>
Figure PCTKR2009007995-appb-I000103
Figure PCTKR2009007995-appb-I000103
상기 실시예 85의 방법에서 벤질알콜(1g, 9.2mmol) 용액 대신 4-시클로헥실-1-부탄올(1g, 6.4mmol) 용액을 사용한 것을 제외하고는 동일한 방법을 수행하여, 중간체 산물인 2-클로로-4-(3-시클로헥실부톡시)벤즈알데히드 1.56g(83% 수율)을 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-4-(3-시클로헥실부톡시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-4-(3-cyclohexylbutoxy)benzylidene)thiazolidine-2,4-dione)(1.02 g, 76% 수율)을 수득하였다. 상기 수득한 유도체 98 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.649(s, 1H), 7.880 (s, 1H), 7.497 (s, 1H), 7.497 (d, J = 9.3 Hz, 1H), 7.515 (d, J = 9.3 Hz, 1H), 3.014 ( t, J= 7.2 Hz, 2H), 1.653-1.724 (m, 4H), 1.315-1.642 (m, 4H), 1.069-1.215 (m, 7H), 0.820 0.852 (m, 2H)이었다. The procedure of Example 85 was repeated except that 4-cyclohexyl-1-butanol (1 g, 6.4 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution. 1.56 g (83% yield) of -4- (3-cyclohexylbutoxy) benzaldehyde was obtained, and the obtained intermediate product was then subjected to 4- (2-cyclomethy in the second step of the derivative preparation of Example 51. 5- (2-Chloro-4- (3-cyclohexylbutoxy) benzylidene) thiazolidine-2,4 represented by the above formula by following the same procedure except that it was used instead of -Dione (5- (2-chloro-4- (3-cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione) (1.02 g, 76% yield) was obtained. The obtained derivative 98 compound isOneH NMR (300 MHz, DMSO-d                 6) δ 12.649 (s, 1 H), 7.880 (s, 1 H), 7.497 (s, 1 H), 7.497 (d,J = 9.3 Hz, 1H), 7.515 (d,J = 9.3 Hz, 1H), 3.014 (t,J= 7.2 Hz, 2H), 1.653-1.724 (m, 4H), 1.315-1.642 (m, 4H), 1.069-1.215 (m, 7H), 0.820 0.852 (m, 2H).
<실시예 99><Example 99>
본 발명에 따른 유도체 99의 제조Preparation of Derivative 99 According to the Invention
하기 화학식으로 나타내는 유도체 99를 다음과 같은 방법으로 제조하였다.     Derivative 99 represented by the following formula was prepared in the following manner.
<유도체 99의 화학식>      <Formula of derivative 99>
Figure PCTKR2009007995-appb-I000104
Figure PCTKR2009007995-appb-I000104
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로헥산올(1g, 10mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.57g, 10mmol)를 사용하며, 트리페닐포스피린을 2.89g, 11mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(시클로헥실옥시)벤즈알데히드 1.69g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 71%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(시클로헥실옥시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(cyclohexyloxy)benzylidene)thiazolidine-2,4-dione)(1.12 g, 78.9% 수율)을 수득하였다. 상기 수득한 유도체 99 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.587 (s, 1H), 7.724 (s, 1H), 7.524 (d, J = 9.3 Hz, 1H), 7.315 (t, 1H), 7.195 (d, J = 9.3 Hz, 1H), 4.310-4.389 (m, 1H), 1.933-2.044 (m, 2H), 1.734-1.822 (m, 2H), 1.491-1.674 (m, 2H), 1.208-1.446 (m, 2H), 0.860-0.946 (m, 2H)이었다. In preparing the derivative of Example 51, cyclohexanol (1 g, 10 mmol) was used instead of cyclohexane methanol, and 2-chloro-3-hydroxy benzaldehyde (1.57 g, instead of 4-hydroxy-3-methylbenzaldehyde). 10 mmol), and 1.69 g of the intermediate product 2-chloro-3- (cyclohexyloxy) benzaldehyde was obtained using the same method except that triphenylphosphine was used in an amount of 2.89 g and 11 mmol, The yield of the intermediate product was 71%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexyloxy) benzylidene) thiazolidine-2,4-dione) (1.12 g, 78.9% yield) was obtained. The obtained derivative 99 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.587 (s, 1H), 7.724 (s, 1H), 7.524 (d, J = 9.3 Hz, 1H), 7.315 (t , 1H), 7.195 (d, J = 9.3 Hz, 1H), 4.310-4.389 (m, 1H), 1.933-2.044 (m, 2H), 1.734-1.822 (m, 2H), 1.491-1.674 (m, 2H ), 1.208-1.446 (m, 2H), 0.860-0.946 (m, 2H).
<실시예 100><Example 100>
본 발명에 따른 유도체 100의 제조Preparation of Derivative 100 According to the Invention
하기 화학식으로 나타내는 유도체 100을 다음과 같은 방법으로 제조하였다.     Derivative 100 represented by the following formula was prepared in the following manner.
<유도체 100의 화학식>      <Formula of derivative 100>
Figure PCTKR2009007995-appb-I000105
Figure PCTKR2009007995-appb-I000105
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-시클로헥실-1-부탄올(1g, 6.4mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.0g, 6.4mmol)를 사용하며, 트리페닐포스피린을 1.85g, 7.04mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(시클로헥실부톡시)벤즈알데히드 1.49g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 79.3%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(시클로헥실부톡시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(cyclohexylbutoxy)benzylidene)thiazolidine-2,4-dione)(1.12 g, 83.6% 수율)을 수득하였다. 상기 수득한 유도체 100 화합물은 1H NMR (300 MHz, DMSO-d 6) δ7.894 (s, 1H), 7.496 (d, J = 9.3 Hz, 1H), 7.264-7.342 (m, 1H), 7.203 (d, J = 9.3 Hz, 1H), 4.103 (t, J = 13.2 Hz, 2H), 1.839-1.913 (m, 2H), 1.569-1.726 (m, 5H), 1.089-1.436 (m, 8H), 0.912-0.998 (m, 2H)이었다.In preparing the derivative of Example 51, 4-cyclohexyl-1-butanol (1 g, 6.4 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxy instead of 4-hydroxy-3-methylbenzaldehyde. Roxybenzaldehyde (1.0 g, 6.4 mmol) was used, and the intermediate product 2-chloro-3- (cyclohexylbutoxy) was obtained using the same method except that triphenylphosphine was used in an amount of 1.85 g and 7.04 mmol. 1.49 g of benzaldehyde was obtained, wherein the yield of the intermediate product was 79.3%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3- (cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (cyclohexylbutoxy) benzylidene) thiazolidine-2,4-dione) (1.12 g, 83.6% yield) was obtained. The obtained derivative 100 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.894 (s, 1H), 7.496 (d, J = 9.3 Hz, 1H), 7.264-7.342 (m, 1H), 7.203 (d, J = 9.3 Hz, 1H), 4.103 (t, J = 13.2 Hz, 2H), 1.839-1.913 (m, 2H), 1.569-1.726 (m, 5H), 1.089-1.436 (m, 8H), 0.912-0.998 (m, 2H).
<실시예 101><Example 101>
본 발명에 따른 유도체 101의 제조Preparation of the derivative 101 according to the present invention
하기 화학식으로 나타내는 유도체 101을 다음과 같은 방법으로 제조하였다.     Derivative 101 represented by the following formula was prepared in the following manner.
<유도체 101의 화학식>      <Formula of derivative 101>
Figure PCTKR2009007995-appb-I000106
Figure PCTKR2009007995-appb-I000106
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-티오펜 에탄올(1g, 7.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.22g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(2-(티오펜-2-일)에톡시)벤즈알데히드 1.56g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 75%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-클로로-4-(2-티오펜-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-4-(2-(thiophen-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione) (1.21 g, 88.3% 수율)을 수득하였다. 상기 수득한 유도체 101 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.585 (s, 1H), 7.725 (s, 1H), 7.708 (d, J = 2.4 Hz, 1H), 7.536 (d, J = 11.1 Hz, 1H), 7.315-7.363 (m, 2H), 7.017 (d, J = 3.3 Hz, 1H), 6.978 (d, J = 8.4 Hz, 1H), 4.354 (t, J = 12.6 Hz, 2H), 3.322 (t, J = 12.6 Hz, 2H)이었다.In the preparation of the derivative of Example 51, 2-thiophene ethanol (1 g, 7.8 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxy-3-methylbenzaldehyde ( 1.22 g, 7.8 mmol), and the intermediate product 3-chloro-4- (2- (thiophen-2) using the same method except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.56 g of -yl) ethoxy) benzaldehyde were obtained, wherein the yield of the intermediate product was 75%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3-chloro-4- (2-thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro-4- (2- (thiophen- 2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) (1.21 g, 88.3% yield) were obtained. The obtained derivative 101 compound was prepared by 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.585 (s, 1H), 7.725 (s, 1H), 7.708 (d, J = 2.4 Hz, 1H), 7.536 (d , J = 11.1 Hz, 1H), 7.315-7.363 (m, 2H), 7.017 (d, J = 3.3 Hz, 1H), 6.978 (d, J = 8.4 Hz, 1H), 4.354 (t, J = 12.6 Hz , 2H), 3.322 (t, J = 12.6 Hz, 2H).
<실시예 102><Example 102>
본 발명에 따른 유도체 102의 제조Preparation of the derivative 102 according to the invention
하기 화학식으로 나타내는 유도체 102를 다음과 같은 방법으로 제조하였다.     Derivative 102 represented by the following formula was prepared in the following manner.
<유도체 102의 화학식>      <Formula of derivative 102>
Figure PCTKR2009007995-appb-I000107
Figure PCTKR2009007995-appb-I000107
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-티오펜 에탄올(1g, 7.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 4-히드록시-3-메톡시벤즈알데히드(1.19g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-메톡시-4-(2-(티오펜-2-일)에톡시)벤즈알데히드 1.62g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 79.4%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(3-메톡시-4-(2-(티오펜-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(3-methoxy-4-(2-(thiophen-2-yl)ethoxy)benzylidene) thiazolidine-2,4-dione) (1.22 g, 88.4% 수율)을 수득하였다. 상기 수득한 유도체 102 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.438 (s, 1H), 7.722 (s, 1H), 7.357 (d, J = 6.6 Hz, 1H), 7.239 (s, 1H), 7.197 (d, J = 14.4 Hz, 2H), 6,946-6.994 (m, 2H), 4.265 (t, J = 6.6 Hz, 2H), 3.803 (s, 3H), 3.269 (t, J = 6.6 Hz, 2H)이었다.In the preparation of the derivative of Example 51, 2-thiophene ethanol (1 g, 7.8 mmol) was used instead of cyclohexanemethanol, and 4-hydroxy-3-methoxybenzaldehyde instead of 4-hydroxy-3-methylbenzaldehyde. (1.19 g, 7.8 mmol), and the intermediate product 3-methoxy-4- (2- (thiophene) using the same method, except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.62 g of 2-yl) ethoxy) benzaldehyde was obtained, with a yield of 79.4% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (3-methoxy-4- (2- (thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (3-methoxy-4- (2- ( thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) (1.22 g, 88.4% yield) were obtained. The obtained derivative 102 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.438 (s, 1H), 7.722 (s, 1H), 7.357 (d, J = 6.6 Hz, 1H), 7.239 (s , 1H), 7.197 (d, J = 14.4 Hz, 2H), 6,946-6.994 (m, 2H), 4.265 (t, J = 6.6 Hz, 2H), 3.803 (s, 3H), 3.269 (t, J = 6.6 Hz, 2H).
<실시예 103><Example 103>
본 발명에 따른 유도체 103의 제조Preparation of Derivative 103 According to the Invention
하기 화학식으로 나타내는 유도체 103을 다음과 같은 방법으로 제조하였다.     A derivative 103 represented by the following formula was prepared in the following manner.
<유도체 103의 화학식>      <Formula of derivative 103>
Figure PCTKR2009007995-appb-I000108
Figure PCTKR2009007995-appb-I000108
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-티오펜 에탄올(1g, 7.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 이소바닐린(1.19g, 7.8mmol)를 사용하며, 트리페닐포스피린을 2.25g, 8.58mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 4-메톡시-3-(2-(티오펜-2-일)에톡시)벤즈알데히드 1.60g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 79.2%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(4-메톡시-3-(2-티오펜-2-일)에톡시)벤질리덴)티아졸리딘-2,4-디온(5-(4-methoxy-3-(2-(thiophen-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione) (1.26 g, 91.3% 수율)을 수득하였다. 상기 수득한 유도체 103 화합물은 1H NMR (300 MHz, DMSO-d 6) δ7.706 (s, 1H), 7.361 (d, J = 6.3 Hz, 1H), 7.232 d(d, J = 1.8 Hz, 1H), 7.171 (d, J = 1.8 Hz, 1H), 7.112 (s, 1H), 6,952-6.994 (m, 2H), 4.237 (t, J = 13.2 Hz, 2H), 3.822 (s, 3H), 3.294 (t, J = 13.2 Hz, 2H)이었다.In the preparation of the derivative of Example 51, 2-thiophene ethanol (1 g, 7.8 mmol) was used instead of cyclohexanemethanol, and isovaniline (1.19 g, 7.8 mmol) was used instead of 4-hydroxy-3-methylbenzaldehyde. And the intermediate product 4-methoxy-3- (2- (thiophen-2-yl) ethoxy) using the same method except that triphenylphosphine was used in an amount of 2.25 g and 8.58 mmol. 1.60 g of benzaldehyde was obtained, with a yield of 79.2% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (4-methoxy-3- (2-thiophen-2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione (5- (4-methoxy-3- (2- (thiophen) -2-yl) ethoxy) benzylidene) thiazolidine-2,4-dione) (1.26 g, 91.3% yield) were obtained. The obtained derivative 103 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ7.706 (s, 1H), 7.361 (d, J = 6.3 Hz, 1H), 7.232 d (d, J = 1.8 Hz, 1H), 7.171 (d, J = 1.8 Hz, 1H), 7.112 (s, 1H), 6,952-6.994 (m, 2H), 4.237 (t, J = 13.2 Hz, 2H), 3.822 (s, 3H), 3.294 (t, J = 13.2 Hz, 2H).
<실시예 104><Example 104>
본 발명에 따른 유도체 104의 제조Preparation of Derivative 104 According to the Invention
하기 화학식으로 나타내는 유도체 104를 다음과 같은 방법으로 제조하였다.      Derivative 104 represented by the following formula was prepared in the following manner.
<유도체 104의 화학식>      <Formula of derivative 104>
Figure PCTKR2009007995-appb-I000109
Figure PCTKR2009007995-appb-I000109
상기 실시예 85의 방법에서 벤질알콜(1g, 9.2mmol) 용액 대신 2-피리딘에탄올(1g, 8.1mmol) 용액을 사용한 것을 제외하고는 동일한 방법을 수행하여, 중간체 산물인 2-클로로-3-[2-(피리딘-2-일)에톡시]벤즈알데히드 1.42g(67% 수율)을 수득하였으며, 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{2-클로로-3-[2-(피리딘-2-일)에톡시]벤질리덴}1,3-티아졸리딘-2,4-디온(5-{2-chloro-3-[2-(pyridin-2-yl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione) (1.1 g, 79.7% 수율)을 수득하였다. 상기 수득한 유도체 104 화합물은 1H NMR (300 MHz, DMSO-d 6 ) δ8.461(s, 1H), 7.966 (s, 1H), 7.722 (t, J = 13.8 Hz, 1H), 6.836-7.291 (m, 6H), 4.008 (d, J = 2.7 Hz, 2H), 2.982-3.033 (m, 2H), 1.185 (t, J = 13.8 Hz, 2H)이었다.The procedure of Example 85 was repeated except that 2-pyridineethanol (1 g, 8.1 mmol) solution was used instead of benzyl alcohol (1 g, 9.2 mmol) solution. The intermediate product 2-chloro-3- [ 1.42 g (67% yield) of 2- (pyridin-2-yl) ethoxy] benzaldehyde were obtained, and the obtained intermediate product was then subjected to 4- (2-cyclo in the second step of the derivative preparation of Example 51. 5- {2-Chloro-3- [2- (pyridin-2-yl) ethoxy] benzylidene} 1 represented by the above formula by following the same method except that methoxy) -3-methylbenzaldehyde was used instead. , 3-thiazolidine-2,4-dione (5- {2-chloro-3- [2- (pyridin-2-yl) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione) ( 1.1 g, 79.7% yield). The obtained derivative 104 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.461 (s, 1H), 7.966 (s, 1H), 7.722 (t, J = 13.8 Hz, 1H), 6.836-7.291 (m, 6H), 4.008 (d, J = 2.7 Hz, 2H), 2.982-3.033 (m, 2H), 1.185 (t, J = 13.8 Hz, 2H).
<실시예 105><Example 105>
본 발명에 따른 유도체 105의 제조Preparation of the derivative 105 according to the present invention
하기 화학식으로 나타내는 유도체 105를 다음과 같은 방법으로 제조하였다.     Derivative 105 represented by the following formula was prepared in the following manner.
<유도체 105의 화학식>      <Formula of derivative 105>
Figure PCTKR2009007995-appb-I000110
Figure PCTKR2009007995-appb-I000110
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 5-(2-히드록시에틸)-4-메틸티아졸(1g, 7.0mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.1g, 7.0mmol)를 사용하며, 트리페닐포스피린을 2.02g, 7.7mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-[2-(4-메틸-1,3-티아졸리딘-5-일)에톡시]벤즈알데히드 1.43g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 77%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{2-클로로-3-[2-(4-메틸-1,3-티아졸리딘-5-일)에톡시]벤질리덴}-1,3-티아졸리딘-2,4-디온( 5-{2-chloro-3-[2-(4-methyl-1,3-thiazolidin-5-yl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione)(1.16 g, 85.9% 수율)을 수득하였다. 상기 수득한 유도체 105 화합물은 1H NMR (300 MHz, DMSO-d 6 ) δ12.726 (s,1H), 8.826 (s, 1H), 7.909 (s, 1H), 7.466 (t, J = 16.2 Hz, 1H), 7.273 (d, J = 7.8 Hz, 1H), 7.162 (d, J = 7.8 Hz, 1H), 4.284 (t, J= 12 Hz, 2H), 3.289 (t, J = 12 Hz, 2H), 2.287 (s, 3H)이었다.In the preparation of the derivative of Example 51, 5- (2-hydroxyethyl) -4-methylthiazole (1 g, 7.0 mmol) was used instead of cyclohexanemethanol, and 4-hydroxy-3-methylbenzaldehyde was used instead. 2-chloro-3-hydroxybenzaldehyde (1.1 g, 7.0 mmol) was used, and the intermediate product 2-chloro- was used in the same manner except that triphenylphosphine was used in an amount of 2.02 g, 7.7 mmol. 1.43 g of 3- [2- (4-methyl-1,3-thiazolidin-5-yl) ethoxy] benzaldehyde were obtained, wherein the yield of the intermediate product was 77%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- {2-chloro-3- [2- (4-methyl-1,3-thiazolidin-5-yl) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione ( 5- {2-chloro-3- [2- (4-methyl-1,3-thiazolidin-5-yl) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione) (1.16 g, 85.9% Yield). The obtained derivative 105 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.726 (s, 1H), 8.826 (s, 1H), 7.909 (s, 1H), 7.466 (t, J = 16.2 Hz , 1H), 7.273 (d, J = 7.8 Hz, 1H), 7.162 (d, J = 7.8 Hz, 1H), 4.284 (t, J = 12 Hz, 2H), 3.289 (t, J = 12 Hz, 2H ), 2.287 (s, 3H).
<실시예 106><Example 106>
본 발명에 따른 유도체 106의 제조Preparation of Derivatives 106 According to the Invention
하기 화학식으로 나타내는 유도체 106을 다음과 같은 방법으로 제조하였다.     Derivative 106 represented by the following formula was prepared in the following manner.
<유도체 106의 화학식>      <Formula of derivative 106>
Figure PCTKR2009007995-appb-I000111
Figure PCTKR2009007995-appb-I000111
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 5-(2-히드록시에틸)-4-메틸티아졸(1g, 7.0mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.1g, 7.0mmol)를 사용하며, 트리페닐포스피린을 2.02g, 7.7mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-[2-(4-메틸-1,3-티아졸리딘-5-일)에톡시]벤즈알데히드 1.52g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 77.6%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{3-클로로-4-[2-(4-메틸-1,3-티아졸리딘-5-일)에톡시]벤질리덴}-1,3-티아졸리딘-2,4-디온(5-{3-chloro-4-[2-(4-methyl-1,3-thiazolidin-5-yl)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione) (1.14g, 84.4% 수율)을 수득하였다. 상기 수득한 유도체 106 화합물은 1H NMR (300 MHz, DMSO-d 6 ) δ12.586 (s, 1H), 8.832 (s, 1H), 7.724 (s, 1H), 7.697 (s, 1H), 7.532 (d, J = 9.0 Hz, 1H), 7.320 (d, J = 9.0 Hz, 1H), 4.318 (t, J = 11.7 Hz, 2H), 3.274 (t, J = 11.7 Hz, 2H), 2.359 (s, 3H)이었다.In the preparation of the derivative of Example 51, 5- (2-hydroxyethyl) -4-methylthiazole (1 g, 7.0 mmol) was used instead of cyclohexanemethanol, and 4-hydroxy-3-methylbenzaldehyde was used instead. 3-chloro-4-hydroxybenzaldehyde (1.1 g, 7.0 mmol) was used, and the intermediate product 3-chloro- was obtained using the same method except that triphenylphosphine was used in an amount of 2.02 g, 7.7 mmol. 1.52 g of 4- [2- (4-methyl-1,3-thiazolidin-5-yl) ethoxy] benzaldehyde were obtained, with a yield of 77.6% of the intermediate product. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- {3-chloro-4- [2- (4-methyl-1,3-thiazolidin-5-yl) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione ( 5- {3-chloro-4- [2- (4-methyl-1,3-thiazolidin-5-yl) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione) (1.14g, 84.4% Yield). The obtained derivative 106 compound is 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.586 (s, 1H), 8.832 (s, 1H), 7.724 (s, 1H), 7.697 (s, 1H), 7.532 (d, J = 9.0 Hz, 1H), 7.320 (d, J = 9.0 Hz, 1H), 4.318 (t, J = 11.7 Hz, 2H), 3.274 (t, J = 11.7 Hz, 2H), 2.359 (s , 3H).
<실시예 107><Example 107>
본 발명에 따른 유도체 107의 제조Preparation of Derivative 107 According to the Invention
하기 화학식으로 나타내는 유도체 107을 다음과 같은 방법으로 제조하였다.     Derivative 107 represented by the following formula was prepared in the following manner.
<유도체 107의 화학식>      <Formula of derivative 107>
Figure PCTKR2009007995-appb-I000112
Figure PCTKR2009007995-appb-I000112
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로펜탄 에탄올(1g, 8.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.38g, 8.8mmol)를 사용하며, 트리페닐포스피린을 2.57, 9.8mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(2-시클로펜틸에톡시)벤즈알데히드 1.75g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 79.2%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[2-클로로-3-(2-시클로펜틸에톡시)벤질리덴]-1,3-티아졸리딘-2,4-디온(5-[2-chloro-3-(2-cyclopentylethoxy)benzylidene]-1,3-thiazolidine-2,4-dione) (1.21 g, 87.1% 수율)을 수득하였다. 상기 수득한 유도체 107 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.992 (s, 1H), 8.192 (s, 1H), 7.729 (t,J=15.9 Hz, 1H), 7.545 (d,J=12.6 Hz, 1H), 7.373 (d,J=12.9 Hz, 1H), 4.382 (t, J=12.9 Hz, 2H), 1.705-2.225 (m, 9H), 1.399-1.473 (m, 2H)이었다.In the preparation of the derivative of Example 51, cyclopentane ethanol (1 g, 8.8 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxybenzaldehyde (1.38 g) instead of 4-hydroxy-3-methylbenzaldehyde. , 8.8 mmol) and 1.75 g of intermediate product 2-chloro-3- (2-cyclopentylethoxy) benzaldehyde using the same method except that triphenylphosphine was used in an amount of 2.57 and 9.8 mmol. Obtained the yield of the intermediate product was 79.2%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- [2-chloro-3- (2-cyclopentylethoxy) benzylidene] -1,3-thiazolidine-2,4-dione (5- [2-chloro-3- (2-cyclopentylethoxy) benzylidene ] -1,3-thiazolidine-2,4-dione) (1.21 g, 87.1% yield). The obtained derivative 107 compound was prepared by 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.992 (s, 1H), 8.192 (s, 1H), 7.729 (t, J = 15.9 Hz, 1H), 7.545 (d , J = 12.6 Hz, 1H), 7.373 (d, J = 12.9 Hz, 1H), 4.382 (t, J = 12.9 Hz, 2H), 1.705-2.225 (m, 9H), 1.399-1.473 (m, 2H) It was.
<실시예 108><Example 108>
본 발명에 따른 유도체 108의 제조Preparation of the derivative 108 according to the invention
하기 화학식으로 나타내는 유도체 108을 다음과 같은 방법으로 제조하였다.     A derivative 108 represented by the following formula was prepared in the following manner.
<유도체 108의 화학식>      <Formula of derivative 108>
Figure PCTKR2009007995-appb-I000113
Figure PCTKR2009007995-appb-I000113
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 시클로펜탄 에탄올(1g, 8.8mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 3-클로로-4-히드록시벤즈알데히드(1.38g, 8.8mmol)를 사용하며, 트리페닐포스피린을 2.57g, 9.8mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 3-클로로-4-(2-시클로펜틸에톡시)벤즈알데히드 1.8g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 81.5%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-[3-클로로-4-(2-시클로펜틸에톡시)벤질리덴]-1,3-티아졸리딘-2,4-디온(5-[3-chloro-4-(2-cyclopentylethoxy)benzylidene]-1,3-thiazolidine-2,4-dione(1.18 g, 84.9% 수율)을 수득하였다. 상기 수득한 유도체 108 화합물은 1H NMR (300 MHz, DMSO-d 6) δ12.992 (s, 1H), 7.720 (s, 1H), 7.689 (s, 1H), 7.545 (d,J=11.1 Hz, 1H), 7.317 (d,J=8.7 Hz, 1H), 4.161 (t, J=13.2 Hz, 2H), 1.189-1.921 (m, 9H), 1.053-1.212 (m, 2H)이었다.In the preparation of the derivative of Example 51, cyclopentane ethanol (1 g, 8.8 mmol) was used instead of cyclohexanemethanol, and 3-chloro-4-hydroxybenzaldehyde (1.38 g) instead of 4-hydroxy-3-methylbenzaldehyde. , 8.8 mmol) and the intermediate product 3-chloro-4- (2-cyclopentylethoxy) benzaldehyde 1.8 using the same method except that triphenylphosphine was used in an amount of 2.57 g and 9.8 mmol. g was obtained, wherein the yield of the intermediate product was 81.5%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- [3-chloro-4- (2-cyclopentylethoxy) benzylidene] -1,3-thiazolidine-2,4-dione (5- [3-chloro-4- (2-cyclopentylethoxy) benzylidene ] -1,3-thiazolidine-2,4-dione (1.18 g, 84.9% yield) The obtained derivative 108 was prepared by 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.992 (s, 1H), 7.720 (s, 1H), 7.689 (s, 1H), 7.545 (d, J = 11.1 Hz, 1H), 7.317 (d, J = 8.7 Hz, 1H), 4.161 (t, J = 13.2 Hz, 2H), 1.189-1.921 (m, 9H), 1.053-1.212 (m, 2H).
<실시예 109><Example 109>
본 발명에 따른 유도체 109의 제조Preparation of Derivative 109 According to the Invention
하기 화학식으로 나타내는 유도체 109를 다음과 같은 방법으로 제조하였다.     Derivative 109 represented by the following formula was prepared in the following manner.
<유도체 109의 화학식>      <Formula of Derivative 109>
Figure PCTKR2009007995-appb-I000114
Figure PCTKR2009007995-appb-I000114
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 4-니트로벤질 알콜(1g, 6.5mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.02g, 6.5mmol)를 사용하며, 트리페닐포스피린을 1.88g, 7.15mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-(4-니트로벤질옥시)벤즈알데히드 1.56g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 82.1%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-(2-클로로-3-(4-니트로벤질옥시)벤질리덴)티아졸리딘-2,4-디온(5-(2-chloro-3-(4-nitrobenzyloxy)benzylidene)thiazolidine-2,4-dione)(1.05 g, 78.4% 수율)을 수득하였다. 상기 방법으로 수득한 유도체 109의 화합물은 1H NMR (300 MHz, DMSO-d 6)δ8.405(s,1H), 8.300(d,J=9Hz,2H), 7.763(d,J=9Hz,2H), 7.451(t,J=8.1Hz,1H), 7.249(t,J=7.5Hz,2H), 5.419(s,2H)이었다.In preparing the derivative of Example 51, 4-nitrobenzyl alcohol (1 g, 6.5 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3-hydroxybenzaldehyde instead of 4-hydroxy-3-methylbenzaldehyde ( 1.02 g, 6.5 mmol) and the intermediate product 2-chloro-3- (4-nitrobenzyloxy) benzaldehyde using the same method except that triphenylphosphine was used in an amount of 1.88 g and 7.15 mmol. 1.56 g were obtained, wherein the yield of the intermediate product was 82.1%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- (2-chloro-3- (4-nitrobenzyloxy) benzylidene) thiazolidine-2,4-dione (5- (2-chloro-3- (4-nitrobenzyloxy) benzylidene) thiazolidine-2,4 -dione) (1.05 g, 78.4% yield) was obtained. Compound of the derivative 109 obtained by the above method was 1 H NMR (300 MHz, DMSO- d 6 ) δ8.405 (s, 1H), 8.300 (d, J = 9Hz, 2H), 7.763 (d, J = 9Hz, 2H), 7.451 (t, J = 8.1 Hz, 1H), 7.249 (t, J = 7.5 Hz, 2H), and 5.419 (s, 2H).
<실시예 110><Example 110>
본 발명에 따른 유도체 110의 제조Preparation of Derivative 110 According to the Invention
하기 화학식으로 나타내는 유도체 110을 다음과 같은 방법으로 제조하였다.     Derivative 110 represented by the following formula was prepared in the following manner.
<유도체 110의 화학식>      <Formula of derivative 110>
Figure PCTKR2009007995-appb-I000115
Figure PCTKR2009007995-appb-I000115
상기 실시예 51의 유도체를 제조하는 과정에서 시클로헥산메탄올 대신 2-(시클로헥실옥시)에탄올(1g, 6.9mmol)을 사용하고, 4-히드록시-3-메틸벤즈알데히드 대신 2-클로로-3-히드록시벤즈알데히드(1.08g, 6.9mmol)를 사용하며, 트리페닐포스피린을 1.99g, 7.59mmol의 양으로 사용한 것을 제외하고는 동일한 방법을 사용하여 중간체 생성물인 2-클로로-3-[2-시클로헥실옥시)에톡시]벤즈알데히드 1.48g을 수득하였으며, 이때 상기 중간체 생성물의 수율은 74.4%이었다. 이후 상기 수득한 중간체 생성물을 상기 실시예 51의 유도체 제조 과정 중 제2 단계에서 4-(2-시클로메톡시)-3-메틸벤즈알데히드 대신 사용한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식으로 표시되는 5-{2-클로로-3-[2-(시클로헥실옥시)에톡시]벤질리덴}-1,3-티아졸리딘-2,4-디온(5-{2-chloro-3-[2-(cyclohexyloxy)ethoxy]benzylidene}-1,3-thiazolidine-2,4-dione)(1.15g, 85.2% 수율)을 수득하였다. 상기 수득한 유도체 110 화합물은 1H NMR (300 MHz, DMSO-d 6)δ7.922 (s, 1H), 7.468 (t, J=15.9 Hz, 1H), 7.298 (d, J=7.5 Hz, 1H), 7.160 (d, J=8.1 Hz, 1H), 4.212 (t, J=9 Hz, 2H), 4.051 (q, 1H), 3.775 (t, J=9 Hz, 2H), 1.63-1.647 (m, 3H), 1.630-1.647 (m, 3H), 1.138-1.464 (m, 4H)이었다.In preparing the derivative of Example 51, 2- (cyclohexyloxy) ethanol (1 g, 6.9 mmol) was used instead of cyclohexanemethanol, and 2-chloro-3- instead of 4-hydroxy-3-methylbenzaldehyde. Hydroxybenzaldehyde (1.08 g, 6.9 mmol) was used, and the intermediate product 2-chloro-3- [2-cyclo was used in the same manner except that triphenylphosphine was used in an amount of 1.99 g and 7.59 mmol. 1.48 g of hexyloxy) ethoxy] benzaldehyde was obtained, wherein the yield of the intermediate product was 74.4%. Thereafter, the obtained intermediate product was represented by the same formula as in the following procedure, except that the second product was used instead of 4- (2-cyclomethoxy) -3-methylbenzaldehyde in the preparation of the derivative of Example 51. 5- {2-chloro-3- [2- (cyclohexyloxy) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione (5- {2-chloro-3- [2 -(cyclohexyloxy) ethoxy] benzylidene} -1,3-thiazolidine-2,4-dione) (1.15 g, 85.2% yield) was obtained. The obtained derivative 110 compound was 1 H NMR (300 MHz, DMSO- d 6 ) δ7.922 (s, 1H), 7.468 (t, J = 15.9 Hz, 1H), 7.298 (d, J = 7.5 Hz, 1H ), 7.160 (d, J = 8.1 Hz, 1H), 4.212 (t, J = 9 Hz, 2H), 4.051 (q, 1H), 3.775 (t, J = 9 Hz, 2H), 1.63-1.647 (m , 3H), 1.630-1.647 (m, 3H), 1.138-1.464 (m, 4H).
<실시예 111><Example 111>
본 발명에 따른 유도체 111의 제조Preparation of the derivative 111 according to the invention
<유도체 111의 화학식> <Formula of derivative 111>
Figure PCTKR2009007995-appb-I000116
Figure PCTKR2009007995-appb-I000116
메탄올 30ml에 상기 실시예 66에서 합성된 메틸-4-((4-((2,4-디옥소티아졸리딘-5-일이덴)메틸)페녹시)시클로헥산카르복실레이트(methyl-4-((4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)methyl)cyclohexanecarboxylate)가 용해된 용액에 2N의 KOH(30 ml)을 첨가하여 교반하였고, 환류 하에서 1시간 동안 상기 혼합물을 교반하였다. 이후 혼합물을 물로 희석하고 염산으로 산성화 시킨 후, 형성된 침전물을 물로 세척한 다음 건조하여 0.74 g의 흰색 고형의 상기 화학식 111로 표시되는 4-({4-[(Z)-(2,4-디옥소-1,3-티아졸리딘-5-일이덴)메틸]페녹시}메틸)시클로헥산카르복실산(4-({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}methyl)cyclohexanecarboxylic acid)을 수득하였다. 상기 수득한 유도체 111 화합물의 수율은 77.1%이었고, 1H NMR (300 MHz, DMSO-d 6) δ 1.947 (s, 1H), 7.427 (d, J=8.7 Hz, 2H), 7.206 (s, 1H), 6.974 (d, J=8.7 Hz, 2H), 3.790 (d, J = 6.9 Hz, 2H), 2.478-2.502 (m, 2H), 1.904-1.918 (m, 4H), 1.461-1.639 (m, 1H), 1.329-1.461 (m, 3H)이었다. Methyl-4-((4-((4-((2,4-dioxothiazolidine-5-ylidene) methyl) phenoxy) cyclohexanecarboxylate (methyl-4) synthesized in Example 66 was added to 30 ml of methanol. To a solution of-((4-((2,4-dioxothiazolidine-5-ylidene) methyl) phenoxy) methyl) cyclohexanecarboxylate) was added with 2N KOH (30 ml) and stirred, and the mixture was refluxed for 1 hour. The mixture was then diluted with water and acidified with hydrochloric acid, the precipitate formed was washed with water and dried to give 0.74 g of a white solid of 4-({4-[( Z )-(2). , 4-dioxo-1,3-thiazolidine-5-ylidene) methyl] phenoxy} methyl) cyclohexanecarboxylic acid (4-({4-[( Z )-(2,4-dioxo -1,3-thiazolidin-5-ylidene) methyl] phenoxy} methyl) cyclohexanecarboxylic acid) The yield of the obtained derivative 111 was 77.1%, 1 H NMR (300 MHz, DMSO- d 6 ) δ 1.947 (s, 1H), 7.427 (d, J = 8.7 Hz, 2H), 7.206 (s, 1H), 6.974 (d , J = 8.7 Hz, 2H), 3.790 (d, J = 6.9 Hz, 2H), 2.478-2.502 (m, 2H), 1.904-1.918 (m, 4H), 1.461-1.639 (m, 1H), 1.329- 1.461 (m, 3 H).
<실시예 112><Example 112>
본 발명에 따른 유도체 112의 제조Preparation of Derivative 112 According to the Invention
하기 화학식으로 나타내는 유도체 112를 다음과 같은 방법으로 제조하였다. Derivative 112 represented by the following formula was prepared in the following manner.
<유도체 112의 화학식> <Formula of derivative 112>
Figure PCTKR2009007995-appb-I000117
Figure PCTKR2009007995-appb-I000117
먼저, 물 10 ml에 CoCl2 6H2O(4.5 mg, 0.016 mmol) 및 디메틸글리옥심(dimethylglyoxime) (70.1mg, 0.6mmol))이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(384.6 mg, 10 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF(2:1, 15 ml) 중의 5-(4-((1-methylcyclohexyl)methoxy)benzylidene)thiazolidine-2,4-dione(1g, 3.0 mmol) 을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 112 유도체인 5-(4-((1-메틸시클로헥실)메톡시)벤질)티아졸리딘-2,4-디온(5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4- dione)(0.8g, 수율:80%)를 정제하였다.First, 1.0 N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.5 mg, 0.016 mmol) and dimethylglyoxime (70.1 mg, 0.6 mmol) dissolved in 10 ml of water. NaBH 4 (384.6 mg, 10 mmol) was then added and the mixture was cooled to 0 ° C. To the mixture was then added 5- (4-((1-methylcyclohexyl) methoxy) benzylidene) thiazolidine-2,4-dione (1 g, 3.0 mmol) in THF-DMF (2: 1, 15 ml) over 20 minutes. And stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was subjected to chromatography over silica gel to give the above formula 112 derivative 5- (4-((1-methylcyclohexyl) methoxy) benzyl) thiazolidine-2,4-dione (5-) as a white solid. (4-((1-methylcyclohexyl) methoxy) benzyl) thiazolidine-2,4-dione) (0.8 g, yield: 80%) was purified.
<실시예 113><Example 113>
본 발명에 따른 유도체 113의 제조Preparation of the derivative 113 according to the invention
하기 화학식으로 나타내는 유도체 113을 다음과 같은 방법으로 제조하였다. Derivative 113 represented by the following formula was prepared in the following manner.
<유도체 113의 화학식> <Formula of derivative 113>
Figure PCTKR2009007995-appb-I000118
Figure PCTKR2009007995-appb-I000118
물 10 ml에 CoCl2 6H2O(4.5 mg, 0.016 mmol) 및 디메틸글리옥심(dimethylglyoxime) (70.1 mg, 0.6 mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(384.6 mg, 10 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후, 상기 혼합액에 THF-DMF(2:1, 15 ml) 중의 5- (4- (2- 사이클로헥실에톡시) 벤질리덴) 티아졸리딘 - 2,4 - 디온 (5- (4- (2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)(1g, 3.02 mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 113의 유도체인 5-(4-(2-시클로헥실에톡시)벤질)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylethoxy)benzyl)thiazolidine-2,4-dione)(0.8g, 수율:79%)를 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ11.998 (s, 1H) 7.135 (d, J = 7.5Hz, 2H), 6.861 (d, J = 7.8 Hz, 2H), 4.870 (dd, J = 3.3, 3.3Hz, 1H), 3.966 (t, J = 12.9Hz, 2H), 3.35 (dd, J = 4.5, 4.5Hz, 1H), 3.07 (dd, J = 9.0, 9.0Hz, 1H), 1.548-1.615 (m, 7H), 1.433-1.548 (m, 1H), 1.097-1.261 (m, 3H), 0.869-0.977 (m, 2H)이었다. 1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.5 mg, 0.016 mmol) and dimethylglyoxime (70.1 mg, 0.6 mmol) in 10 ml of water, followed by NaBH 4 (384.6 mg, 10 mmol) was added and the mixture was cooled to 0 ° C. Then to the mixture was added 5- (4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2) in THF-DMF (2: 1, 15 ml). -cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione) (1 g, 3.02 mmol) was added over 20 minutes and stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was subjected to chromatography over silica gel to give a white solid, derivative of formula 113, 5- (4- (2-cyclohexylethoxy) benzyl) thiazolidine-2,4-dione (5- (4). -(2-cyclohexylethoxy) benzyl) thiazolidine-2,4-dione) (0.8 g, yield: 79%) was purified. 1 H NMR of this derivative (300 MHz, DMSO-d 6 ) is δ 11.998 (s, 1 H) 7.135 (d, J = 7.5 Hz, 2H), 6.861 (d, J = 7.8 Hz, 2H), 4.870 ( dd, J = 3.3, 3.3 Hz, 1H), 3.966 (t, J = 12.9 Hz, 2H), 3.35 (dd, J = 4.5, 4.5 Hz, 1H), 3.07 (dd, J = 9.0, 9.0 Hz, 1H ), 1.548-1.615 (m, 7H), 1.433-1.548 (m, 1H), 1.097-1.261 (m, 3H), 0.869-0.977 (m, 2H).
<실시예 114><Example 114>
본 발명에 따른 유도체 114의 제조Preparation of Derivative 114 According to the Invention
하기 화학식으로 나타내는 유도체 114를 다음과 같은 방법으로 제조하였다. Derivative 114 represented by the following formula was prepared in the following manner.
<유도체 114의 화학식> <Formula of derivative 114>
Figure PCTKR2009007995-appb-I000119
Figure PCTKR2009007995-appb-I000119
물 10ml에 CoCl2 6H2O(4.4 mg, 0.016 mmol) 및 디메틸글리옥심(dimethylglyoxime) (73.1 mg, 0.58 mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(409.3 mg, 10.6 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.4 mg, 0.016 mmol) and dimethylglyoxime (73.1 mg, 0.58 mmol) in 10 ml of water, followed by NaBH 4 ( 409.3 mg, 10.6 mmol) was added and the mixture was cooled to 0 ° C.
이후 상기 혼합액에 THF-DMF(2:1, 15 ml) 중의5-(4-(2-사이클로헥실메톡시)벤질리덴)티아졸리딘-2,4-디온 5-(4-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione (1g,3.13 mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 114의 유도체인 5-(4-(시클로헥실메톡시)벤질)티아졸리딘-2,4-디온(5-(4-(cyclohexylmethoxy)benzyl)thiazolidine-2,4-dione)(0.8g, 수율:79%)를 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ7.816 (s, 1H), 7.145 (d, J = 8.7Hz, 2H), 6.854 (d, J = 8.7Hz, 2H), 4.528 (dd, J = 3.6, 3.6Hz, 1H), 3.740 (d, J = 6.6Hz, 2H), 3.486 (dd, J = 4.2, 4.2Hz, 1H), 3.138 (dd, J = 9.6, 9.6Hz, 1H), 1.604-1.882 (m, 6H), 1.212-1.426 (m, 3H), 0.884-1.131 (m, 2H)이었다. The mixture was then added with 5- (4- (2-cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione 5- (4- (cyclohexylmethoxy) benzylidene in THF-DMF (2: 1, 15 ml). ) thiazolidine-2,4-dione (1 g, 3.13 mmol) was added over 20 minutes and stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was subjected to chromatography over silica gel to give a derivative of the formula 114 as a white solid, 5- (4- (cyclohexylmethoxy) benzyl) thiazolidine-2,4-dione (5- (4- ( Cyclohexylmethoxy) benzyl) thiazolidine-2,4-dione) (0.8 g, yield: 79%) was purified. 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) is shown at δ 7.816 (s, 1H), 7.145 (d, J = 8.7 Hz, 2H), 6.854 (d, J = 8.7 Hz, 2H), 4.528 (dd, J = 3.6, 3.6 Hz, 1H), 3.740 (d, J = 6.6 Hz, 2H), 3.486 (dd, J = 4.2, 4.2 Hz, 1H), 3.138 (dd, J = 9.6, 9.6 Hz, 1H), 1.604-1.882 (m, 6H), 1.212-1.426 (m, 3H), 0.884-1.131 (m, 2H).
<실시예 115><Example 115>
본 발명에 따른 유도체 115의 제조Preparation of Derivative 115 According to the Invention
하기 화학식으로 나타내는 유도체 115를 다음과 같은 방법으로 제조하였다. Derivative 115 represented by the following formula was prepared in the following manner.
<유도체 115의 화학식> <Formula of derivative 115>
Figure PCTKR2009007995-appb-I000120
Figure PCTKR2009007995-appb-I000120
물 10ml에 CoCl2 6H2O(4.6 mg, 0.016 mmol) 및 디메틸글리옥심(dimethylglyoxime) (76.4 mg, 0.65 mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(427.6 mg, 11.12 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF(2:1, 15ml) 중의 5-(4-(cyclopentylmethoxy)benzylidene)thiazolidine-2,4-dione (1g,3.27 mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 115의 유도체인 5-(4-(시클로펜틸메톡시)벤질)티아졸리딘-2,4-디온(5-(4-(cyclopentylmethoxy)benzyl)thiazolidine-2,4-dione)(0.8g, 수율:79%)을 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ7.842 (s, 1H), 7.146 (d, J = 8.7Hz, 2H), 6.874 (d, J = 8.7 Hz, 2H), 4.531(dd, J = 4.2, 4.2Hz, 1H), 3.819(d, J = 6.9Hz, 2H), 3.482 (dd, J = 4.2, 4.2Hz, 1H), 3.145 (dd, J = 9.3, 9.3Hz, 1H), 2.054-2.402 (m, 1H), 1.799-1.867 (m, 2H), 1.565-1.646 (m, 4H), 1.319-1.384 (m, 2H)이었다. 1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.6 mg, 0.016 mmol) and dimethylglyoxime (76.4 mg, 0.65 mmol) in 10 ml of water, followed by NaBH 4 ( 427.6 mg, 11.12 mmol) was added and the mixture was cooled to 0 ° C. To the mixture was added 5- (4- (cyclopentylmethoxy) benzylidene) thiazolidine-2,4-dione (1 g, 3.27 mmol) in THF-DMF (2: 1, 15 ml) over 20 minutes, and 18 hours at room temperature. Was stirred. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was subjected to chromatography over silica gel to give a derivative of the formula 115 as a white solid, 5- (4- (cyclopentylmethoxy) benzyl) thiazolidine-2,4-dione (5- (4- ( Cyclopentylmethoxy) benzyl) thiazolidine-2,4-dione) (0.8 g, yield: 79%) was purified. The 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) is δ 7.842 (s, 1 H), 7.146 (d, J = 8.7 Hz, 2H), 6.874 (d, J = 8.7 Hz, 2H), 4.531 (dd, J = 4.2, 4.2 Hz, 1H), 3.819 (d, J = 6.9 Hz, 2H), 3.482 (dd, J = 4.2, 4.2 Hz, 1H), 3.145 (dd, J = 9.3, 9.3 Hz, 1H), 2.054-2.402 (m, 1H), 1.799-1.867 (m, 2H), 1.565-1.646 (m, 4H), 1.319-1.384 (m, 2H).
<실시예 116><Example 116>
본 발명에 따른 유도체 116의 제조Preparation of Derivative 116 According to the Invention
하기 화학식으로 나타내는 유도체 116을 다음과 같은 방법으로 제조하였다. Derivative 116 represented by the following formula was prepared in the following manner.
<유도체 116의 화학식> <Formula of Derivative 116>
Figure PCTKR2009007995-appb-I000121
Figure PCTKR2009007995-appb-I000121
물 10 ml에 CoCl2 6H2O(4.49 mg, 0.016 mmol) 및 디메틸글리옥심(dimethylglyoxime) (74.54 mg, 0.64 mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(417.1 mg, 10.85 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF(2:1, 15 ml) 중의 5-(4-(benzyloxy)benzylidene)thiazolidine-2,4-dione (1g, 3.19 mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 116로 표시되는 유도체 화합물인 5-(4-(벤질옥시)벤질)티아졸리딘-2,4-디온(5-(4-(benzyloxy)benzyl)thiazolidine-2,4-dione)(0.8g, 수율:79%)을 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ7.85 (s, 1H), 7.262-7.444 (m, 5H), 7.167 (d, J = 8.7Hz, 2H), 6.947 (d, J = 8.7 Hz, 2H), 5.052(s, 2H), 4.533(dd, J = 3.9, 3.9Hz, 1H), 3.487 (dd, J = 3.6, 3.6Hz, 1H), 3.156 (dd, J = 9.0, 9.0Hz, 1H) 이었다.1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.49 mg, 0.016 mmol) and dimethylglyoxime (74.54 mg, 0.64 mmol) in 10 ml of water, followed by NaBH 4 (417.1 mg, 10.85 mmol) was added and the mixture was cooled to 0 ° C. To the mixture was then added 5- (4- (benzyloxy) benzylidene) thiazolidine-2,4-dione (1 g, 3.19 mmol) in THF-DMF (2: 1, 15 ml) over 20 minutes, 18 at room temperature. Stir for hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was subjected to chromatography over silica gel to yield a white solid, 5- (4- (benzyloxy) benzyl) thiazolidine-2,4-dione (5- (4-) (benzyloxy) benzyl) thiazolidine-2,4-dione) (0.8 g, yield: 79%) was purified. The 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) is δ 7.85 (s, 1 H), 7.262-7.444 (m, 5H), 7.167 (d, J = 8.7 Hz, 2H), 6.947 (d, J = 8.7 Hz, 2H), 5.052 (s, 2H), 4.533 (dd, J = 3.9, 3.9 Hz, 1H), 3.487 (dd, J = 3.6, 3.6 Hz, 1H), 3.156 (dd, J = 9.0 , 9.0 Hz, 1H).
<실시예 117><Example 117>
본 발명에 따른 유도체 117의 제조Preparation of Derivative 117 According to the Invention
하기 화학식으로 나타내는 유도체 117을 다음과 같은 방법으로 제조하였다. Derivative 117 represented by the following formula was prepared in the following manner.
<유도체 117의 화학식> <Formula of Derivative 117>
Figure PCTKR2009007995-appb-I000122
Figure PCTKR2009007995-appb-I000122
물 10 ml에 CoCl2 6H2O (3.98 mg, 0.014 mmol) 및 디메틸글리옥심(dimethylglyoxime) (66.13 mg, 0.57 mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(370.06 mg, 9.62 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF(2:1, 15 ml) 중의 5-(3-chloro-4-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione (1g, 2.83 mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 117로 표시되는 화합물인 5-(3-클로로-4-(시클로헥실메톡시)벤질)티아졸리딘-2,4-디온(5-(3-chloro-4-(cyclohexylmethoxy)benzyl)thiazolidine -2,4-dione)(0.8g, 수율:79%)을 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ7.891(s, 1H), 7.238(s, 1H), 7.072 (d, J = 10.8Hz, 2H), 6.854 (d, J = 10.8 Hz, 2H), 4.521(dd, J = 3.6, 3.6Hz, 1H), 3.807 (d, J = 6.3 Hz, 2H), 3.444 (dd, J = 3.6, 3.6 Hz, 1H) 3.129(dd, J = 9.0, 9.0Hz, 1H), 1.693-1.917 (m, 6H), 1.252-1.376 (m, 3H), 1.057-1.211 (m, 2H) 이었다. 1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (3.98 mg, 0.014 mmol) and dimethylglyoxime (66.13 mg, 0.57 mmol) in 10 ml of water, followed by NaBH 4 (370.06 mg, 9.62 mmol) was added and the mixture was cooled to 0 ° C. To the mixture was then added 5- (3-chloro-4- (cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione (1 g, 2.83 mmol) in THF-DMF (2: 1, 15 ml) over 20 minutes. And stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residual oil was chromatographed through silica gel, which was a white solid, 5- (3-chloro-4- (cyclohexylmethoxy) benzyl) thiazolidine-2,4-dione ( 5- (3-chloro-4- (cyclohexylmethoxy) benzyl) thiazolidine-2,4-dione) (0.8 g, yield: 79%) was purified. The 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) is δ 7.891 (s, 1H), 7.238 (s, 1H), 7.072 (d, J = 10.8 Hz, 2H), 6.854 (d, J = 10.8 Hz, 2H), 4.521 (dd, J = 3.6, 3.6 Hz, 1H), 3.807 (d, J = 6.3 Hz, 2H), 3.444 (dd, J = 3.6, 3.6 Hz, 1H) 3.129 (dd, J = 9.0, 9.0 Hz, 1H), 1.693-1.917 (m, 6H), 1.252-1.376 (m, 3H), 1.057-1.211 (m, 2H).
<실시예 118><Example 118>
본 발명에 따른 유도체 118의 제조Preparation of Derivative 118 According to the Invention
하기 화학식으로 나타내는 유도체 118을 다음과 같은 방법으로 제조하였다. Derivative 118 represented by the following formula was prepared in the following manner.
<유도체 118의 화학식> <Formula of Derivative 118>
Figure PCTKR2009007995-appb-I000123
Figure PCTKR2009007995-appb-I000123
물 10 ml에 CoCl2 6H2O(4.77 mg, 0.016 mmol) 및 디메틸글리옥심(dimethylglyoxime) (73.14 mg, 0.63 mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(409.4 mg, 10.65 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF(2:1, 15 ml) 중의 5-(4-(2-cyclopentylethoxy)benzylidene)thiazolidine-2,4-dione (1g, 3.13 mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 118의 유도체인 5-(4-(2-시클로펜틸에톡시)벤질)티아졸리딘-2,4-디온(5-(4-(2-cyclopentylethoxy)benzyl)thiazolidine-2,4-dione)(0.8g, 수율:79%)을 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ7.844 (s, 1H), 7.148 (d, J = 8.4 Hz, 2H), 6.870 (d, J = 8.4 Hz, 2H), 4.529(dd, J = 3.6, 3.6Hz, 1H), 3.980(t, J = 13.5Hz, 2H), 3.485(dd, J = 3.9, 3.9Hz, 1H), 3.143(dd, J = 9.6, 9.6Hz, 1H), 1.869-1.967 (m, 1H), 1.810-1.845(m, 1H), 1.764-1.787 (t, J = 13.5 Hz, 2H), 1.510-1.664 (m, 5H), 1.125-1.192 (m, 2H)이었다.1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (4.77 mg, 0.016 mmol) and dimethylglyoxime (73.14 mg, 0.63 mmol) in 10 ml of water, followed by NaBH 4 (409.4 mg, 10.65 mmol) was added and the mixture was cooled to 0 ° C. To the mixture was then added 5- (4- (2-cyclopentylethoxy) benzylidene) thiazolidine-2,4-dione (1 g, 3.13 mmol) in THF-DMF (2: 1, 15 ml) over 20 minutes. Stir at 18 h. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was subjected to chromatography over silica gel to yield a white solid, 5- (4- (2-cyclopentylethoxy) benzyl) thiazolidine-2,4-dione (5- (4) -(2-cyclopentylethoxy) benzyl) thiazolidine-2,4-dione) (0.8 g, yield: 79%) was purified. 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) was obtained at δ 7.844 (s, 1 H), 7.148 (d, J = 8.4 Hz, 2H), 6.870 (d, J = 8.4 Hz, 2H), 4.529 (dd, J = 3.6, 3.6 Hz, 1H), 3.980 (t, J = 13.5 Hz, 2H), 3.485 (dd, J = 3.9, 3.9 Hz, 1H), 3.143 (dd, J = 9.6, 9.6 Hz, 1H), 1.869-1.967 (m, 1H), 1.810-1.845 (m, 1H), 1.764-1.787 (t, J = 13.5 Hz, 2H), 1.510-1.664 (m, 5H), 1.125-1.192 (m, 2H).
<실시예 119><Example 119>
본 발명에 따른 유도체 119의 제조Preparation of Derivative 119 According to the Invention
하기 화학식으로 나타내는 유도체 119를 다음과 같은 방법으로 제조하였다. Derivative 119 represented by the following formula was prepared in the following manner.
<유도체 119의 화학식> <Formula of derivative 119>
Figure PCTKR2009007995-appb-I000124
Figure PCTKR2009007995-appb-I000124
물 10 ml에 CoCl2 6H2O(3.66 mg, 0.013 mmol) 및 디메틸글리옥심(dimethylglyoxime) (60.75 mg, 0.52 mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(340.11 mg, 8.84 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF (2:1, 15 ml) 중의 5-(4-(2-thiomorpholine1,1-dioxideethoxy)benzylidene)-2,4-thiazolidinedione (1g, 2.6 mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 119로 표시되는 유도체 화합물인 5-(4-(2-티오모르폴린 1,1-디옥시드에톡시)벤질)-2,4-티아졸리딘디온(5-(4-(2-Thiomorpholine1,1-dioxideethoxy)benzyl)-2,4-thiazolidinedione)(0.8g, 수율:79%)을 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ12.308 (s, 1H), 7.568 (d, J = 9.3 Hz, 2H), 6.893 (d, J = 9.3 Hz, 2H), 4.887(dd, J = 4.2, 4.2Hz, 1H), 4.183 (t, J = 11.4Hz, 2H), 4.069 (t, J = 11.4Hz, 2H), 3.095 (d, J = 7.2Hz, 4H), 3.039 (d, J = 7.2Hz, 4H), 2.957 (m, 2H)이었다.1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (3.66 mg, 0.013 mmol) and dimethylglyoxime (60.75 mg, 0.52 mmol) in 10 ml of water, followed by NaBH 4 (340.11 mg, 8.84 mmol) was added and the mixture was cooled to 0 ° C. To the mixture was then added 5- (4- (2-thiomorpholine1,1-dioxideethoxy) benzylidene) -2,4-thiazolidinedione (1 g, 2.6 mmol) in THF-DMF (2: 1, 15 ml) over 20 minutes. And stirred at room temperature for 18 hours. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil was subjected to chromatography over silica gel to give a derivative of the compound represented by the above formula (119), which is a white solid, 5- (4- (2-thiomorpholine 1,1-dioxideethoxy) benzyl) -2,4 -Tazolidinedione (5- (4- (2-Thiomorpholine1,1-dioxideethoxy) benzyl) -2,4-thiazolidinedione) (0.8 g, yield: 79%) was purified. The 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) is δ 12.308 (s, 1H), 7.568 (d, J = 9.3 Hz, 2H), 6.893 (d, J = 9.3 Hz, 2H), 4.887 (dd, J = 4.2, 4.2 Hz, 1H), 4.183 (t, J = 11.4 Hz, 2H), 4.069 (t, J = 11.4 Hz, 2H), 3.095 (d, J = 7.2 Hz, 4H), 3.039 (d, J = 7.2 Hz, 4H), 2.957 (m, 2H).
<실시예 120><Example 120>
본 발명에 따른 유도체 120의 제조Preparation of Derivative 120 According to the Invention
하기 화학식으로 나타내는 유도체 120을 다음과 같은 방법으로 제조하였다. Derivative 120 represented by the following formula was prepared in the following manner.
<유도체 120의 화학식> <Formula of derivative 120>
Figure PCTKR2009007995-appb-I000125
Figure PCTKR2009007995-appb-I000125
물 10 ml에 CoCl2 6H2O (3.83 mg, 0.014 mmol) 및 디메틸글리옥심(dimethylglyoxime) (63.56 mg, 0.54 mmol)이 용해된 현탁액에 1.0N NaOH(4 방울)을 첨가한 후, 이어서 NaBH4(355.43 mg, 9.24 mmol)를 첨가하였고, 상기 혼합액을 0℃까지 냉각시켰다. 이후 상기 혼합액에 THF-DMF (2:1, 15 ml) 중의 5-(3-chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione (1g, 2.72 mmol)을 20분에 걸쳐 첨가하였고, 상온에서 18시간 동안 교반하였다. 이후 상기 혼합액의 pH가 약 6이 될 때까지 아세트산을 첨가하였다. 상기 혼합액은 물로 희석한 다음 에틸 아세테이트 및 물을 이용하여 추출하였다. 유기층은 물을 이용하여 여러번 세척하였고, 무수화 황산마그네슘을 사용하여 건조시켰으며, 여과하고 용매를 증발시켰다. 잔여 오일은 실리카 겔을 통한 크로마토그래피를 통해 백색의 고체인 상기 화학식 120로 표시되는 유도체 화합물인 5-(3-클로로-4-(2-시클로헥실에톡시)벤질)티아졸리딘-2,4-디온(5-(3-chloro-4-(2-cyclohexylethoxy)benzyl)thiazolidine-2,4-dione)(0.8g, 수율:79%)을 정제하였다. 상기 유도체의 1H NMR (300 MHz, DMSO-d6)은 δ7.900(s, 1H), 7.242(s, 1H), 7.078 (d, J = 10.8 Hz, 2H), 6.913 (d, J = 10.8 Hz, 2H), 4.523 (dd, J = 3.9, 3.9 Hz, 1H), 4.068 (t, J = 13.5Hz, 2H), 3.447 (dd, J = 4.2, 4.2Hz, 1H), 3.134(dd, J = 9.3, 9.3 Hz, 1H), 1.689-1.793 (m, 7H), 1.504-1.572 (m, 1H), 1.144-1.329 (m, 3H), 0.926-1.037 (m, 2H) 이었다. 1.0N NaOH (4 drops) was added to a suspension of CoCl 2 6H 2 O (3.83 mg, 0.014 mmol) and dimethylglyoxime (63.56 mg, 0.54 mmol) in 10 ml of water, followed by NaBH 4 (355.43 mg, 9.24 mmol) was added and the mixture was cooled to 0 ° C. Subsequently, 5- (3-chloro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (1 g, 2.72 mmol) in THF-DMF (2: 1, 15 ml) was added to the mixed solution over 20 minutes. It was added and stirred for 18 hours at room temperature. Then acetic acid was added until the pH of the mixture was about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The remaining oil is chromatographed through silica gel, which is a white solid, 5- (3-chloro-4- (2-cyclohexylethoxy) benzyl) thiazolidine-2,4 which is a derivative compound represented by the above formula (120). -Dione (5- (3-chloro-4- (2-cyclohexylethoxy) benzyl) thiazolidine-2,4-dione) (0.8 g, yield: 79%) was purified. 1 H NMR of the derivative (300 MHz, DMSO-d 6 ) is δ7.900 (s, 1H), 7.242 (s, 1H), 7.078 (d, J = 10.8 Hz, 2H), 6.913 (d, J = 10.8 Hz, 2H), 4.523 (dd, J = 3.9, 3.9 Hz, 1H), 4.068 (t, J = 13.5 Hz, 2H), 3.447 (dd, J = 4.2, 4.2 Hz, 1H), 3.134 (dd, J = 9.3, 9.3 Hz, 1H), 1.689-1.793 (m, 7H), 1.504-1.572 (m, 1H), 1.144-1.329 (m, 3H), 0.926-1.037 (m, 2H).
<실시예 121><Example 121>
본 발명에 따른 유도체 121의 제조Preparation of Derivative 121 According to the Invention
하기 화학식으로 나타내는 유도체 121을 다음과 같은 방법으로 제조하였다. Derivative 121 represented by the following formula was prepared in the following manner.
<유도체 121의 화학식> <Formula of derivative 121>
Figure PCTKR2009007995-appb-I000126
Figure PCTKR2009007995-appb-I000126
상기 실시예 120에서 CoCl2·6H2O을 4.32 mg, 0.015 mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 67.31 mg, 0.58m mol 사용하였으며, NaBH4를 369.3 mg, 9.86 mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(4-(2-시클로헥실에톡시)-3-메틸벤질리덴) 티아졸리딘-2,4-디온(5-(4-(2-cyclohexylethoxy)-3-methylbenzylidene)thiazolidine-2,4-dione)(1 g, 2.9 mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 121의 5-(4-(2-시클로헥실에톡시)-3-메틸벤질)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylethoxy)-3-methylbenzyl)thiazolidine-2,4-dione) 화합물(0.8g, 수율:80%)을 수득하였다. 또한, 상기 수득한 유도체 121의 화합물은 1H NMR (300 MHz, CDCl3)δ7.89(s, 1H), 7.346(s, 1H), 7.124(d, J=8.7Hz, 1H), 7.006(d, J=8.7Hz, 1H), 4.623(dd, J=3.9, 4.2Hz, 1H), 4.268(t, J=13.5Hz, 2H), 3.549(dd, J=4.2, 3.9Hz, 1H), 3.244(dd, J=9.6, 9.6Hz, 1H), 2.206(s, 3H), 1.598-1.693(m, 6H), 1.526-1.548(m, 1H), 1.269-1.304(m,4H), 0.838-0.987(m, 2H)이었다. 4.120 mg, 0.015 mmol of CoCl 2 .6H 2 O was used in Example 120, 67.31 mg, 0.58 mmol of dimethylglyoxime was used, and 369.3 mg, 9.86 mmol of NaBH 4 was added to prepare a mixed solution. The mixture was then mixed with 5- (4- (2-cyclohexylethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- () in THF-DMF (2: 1, 15 ml). Except for adding 4- (2-cyclohexylethoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (1 g, 2.9 mmol) over 20 minutes, 4- (2-cyclohexylethoxy) -3-methylbenzyl) thiazolidine-2,4-dione (5- (4- (2-cyclohexylethoxy) -3-methylbenzyl) thiazolidine-2,4-dione) compound (0.8 g, yield: 80%) was obtained. In addition, the compound of the obtained derivative 121 is 1 H NMR (300 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.346 (s, 1H), 7.124 (d, J = 8.7 Hz, 1H), 7.006 ( d, J = 8.7 Hz, 1H), 4.623 (dd, J = 3.9, 4.2 Hz, 1H), 4.268 (t, J = 13.5 Hz, 2H), 3.549 (dd, J = 4.2, 3.9 Hz, 1H), 3.244 (dd, J = 9.6, 9.6 Hz, 1H), 2.206 (s, 3H), 1.598-1.693 (m, 6H), 1.526-1.548 (m, 1H), 1.269-1.304 (m, 4H), 0.838- 0.987 (m, 2 H).
<실시예 122><Example 122>
본 발명에 따른 유도체 122의 제조Preparation of Derivatives 122 According to the Invention
하기 화학식으로 나타내는 유도체 122를 다음과 같은 방법으로 제조하였다. Derivative 122 represented by the following formula was prepared in the following manner.
<유도체 122의 화학식> <Formula of derivative 122>
Figure PCTKR2009007995-appb-I000127
Figure PCTKR2009007995-appb-I000127
상기 실시예 120에서 CoCl2·6H2O을 3.87 mg, 0.013 mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 60.35 mg, 0.52 mmol 사용하였으며, NaBH4를 331.11 mg, 8.84 mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15 ml) 중의 5-(3-클로로-4-(시클로헥실프로폭시)벤질리덴)티아졸리딘-2,4-디온(5-(3-chloro-4-(cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)(1g, 2.6 mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 122의 5-(3-클로로-4-(시클로헥실프로폭시)벤질)티아졸리딘-2,4-디온( 5-(3-chloro-4-(cyclohexylpropoxy)benzyl)thiazolidine-2,4-dione)(0.78g, 수율:77.8%) 화합물을 수득하였다. 또한, 상기 수득한 유도체 122의 화합물은 분석결과, 1H NMR (300 MHz, CDCl3)δ7.91(s, 1H), 7.285(s, 1H), 7.224(d, J=8.4Hz, 1H), 7.108(d, J=8.4Hz, 1H), 4.572(dd, J=3.9, 4.2Hz, 1H), 4.197(t, J=12.6Hz, 2H), 3.487(dd, J=4.2, 3.9Hz, 1H), 3.288(dd, J=9.6, 9.6Hz, 1H), 1.697-1.845(m, 7H), 1.428-1.590(m, 6H), 0.864-0.996(m, 2H) 이었다.3.87 mg, 0.013 mmol of CoCl 2 .6H 2 O was used in Example 120, and dimethylglyoxime was used at 60.35 mg, 0.52 mmol, and NaBH 4 was added to 331.11 mg and 8.84 mmol to prepare a mixed solution. The mixture was then poured into 5- (3-chloro-4- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (3-) in THF-DMF (2: 1, 15 ml). 5- (3-chloro- of Chemical Formula 122 was carried out in the same manner as in the above, except that chloro-4- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (1 g, 2.6 mmol) was added over 20 minutes. 4- (cyclohexylpropoxy) benzyl) thiazolidine-2,4-dione (5- (3-chloro-4- (cyclohexylpropoxy) benzyl) thiazolidine-2,4-dione) (0.78g, yield: 77.8% ) Compound was obtained. In addition, the obtained compound of Derivative 122 was analyzed by 1 H NMR (300 MHz, CDCl 3 ) δ7.91 (s, 1H), 7.285 (s, 1H), 7.224 (d, J = 8.4Hz, 1H). , 7.108 (d, J = 8.4 Hz, 1H), 4.572 (dd, J = 3.9, 4.2 Hz, 1H), 4.197 (t, J = 12.6 Hz, 2H), 3.487 (dd, J = 4.2, 3.9 Hz, 1H), 3.288 (dd, J = 9.6, 9.6 Hz, 1H), 1.697-1.845 (m, 7H), 1.428-1.590 (m, 6H), 0.864-0.996 (m, 2H).
<실시예 123><Example 123>
본 발명에 따른 유도체 123의 제조Preparation of Derivative 123 According to the Invention
하기 화학식으로 나타내는 유도체 123을 다음과 같은 방법으로 제조하였다. Derivative 123 represented by the following formula was prepared in the following manner.
<유도체 123의 화학식> <Formula of Derivative 123>
Figure PCTKR2009007995-appb-I000128
Figure PCTKR2009007995-appb-I000128
상기 실시예 120에서 CoCl2·6H2O을 4.92mg, 0.017mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 76.60mg, 0.66mmol 사용하였으며, NaBH4를 420.3mg, 11.22mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(4-(시클로펜틸메톡시) 벤질리덴) 티아졸리딘 -2,4- 디온(5-(4-(cyclopentylmethoxy)benzylidene)thiazolidine-2,4-dione)(1g,3.3mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 123의 5-(4-(시클로펜틸메톡시)벤질)티아졸리딘-2,4-디온(5-(4-(cyclopentylmethoxy)benzyl)thiazolidine-2,4-dione) 화합물(0.79g, 수율:78.6%)을 수득하였다. 또한, 상기 수득한 유도체 123의 화합물은 1H NMR (300 MHz, CDCl3)δ7.742(s,1H), 7.146(d,J=8.7Hz,2H), 6.874(d,J=8.7Hz,2H), 4.531(dd,J=4.2,4.2Hz,1H),3.819(d,J=6.9Hz,2H),3.469(dd,J=3.9,3.6Hz,1H),3.145(dd,J=9.3,9.6Hz,1H),2.302-2.402(m,1H),1.799-1.867(m,2H),1.565-1.646(m,4H),1.319-1.384(m,2H)이었다.In Example 120, 4.92 mg and 0.017 mmol of CoCl 2 .6H 2 O were used, 76.60 mg and 0.66 mmol of dimethylglyoxime were used, and 420.3 mg and 11.22 mmol of NaBH 4 were added to prepare a mixed solution. Then, 5- (4- (cyclopentylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (cyclopentylmethoxy) benzylidene) in THF-DMF (2: 1, 15 ml) was added to the mixed solution. 5- (4- (cyclopentylmethoxy) benzyl) thiazolidine of Formula 123 was carried out in the same manner except that thiazolidine-2,4-dione) (1 g, 3.3 mmol) was added over 20 minutes. -2,4-dione (5- (4- (cyclopentylmethoxy) benzyl) thiazolidine-2,4-dione) compound (0.79 g, yield: 78.6%) was obtained. In addition, the obtained compound of Derivative 123 was 1 H NMR (300 MHz, CDCl 3 ) δ7.742 (s, 1H), 7.146 (d, J = 8.7Hz, 2H), 6.874 (d, J = 8.7Hz, 2H), 4.531 (dd, J = 4.2, 4.2 Hz, 1H), 3.819 (d, J = 6.9 Hz, 2H), 3.469 (dd, J = 3.9, 3.6 Hz, 1H), 3.145 (dd, J = 9.3) , 9.6 Hz, 1H), 2.232-2.402 (m, 1H), 1.799-1.867 (m, 2H), 1.565-1.646 (m, 4H), and 1.319-1.384 (m, 2H).
<실시예 124><Example 124>
본 발명에 따른 유도체 124의 제조Preparation of Derivative 124 According to the Invention
하기 화학식으로 나타내는 유도체 124를 다음과 같은 방법으로 제조하였다. Derivative 124 represented by the following formula was prepared in the following manner.
<유도체 124의 화학식> <Formula of Derivative 124>
Figure PCTKR2009007995-appb-I000129
Figure PCTKR2009007995-appb-I000129
상기 실시예 120에서 CoCl2·6H2O을 4.77mg, 0.016mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 74.29mg, 0.64mmol 사용하였으며, NaBH4를 407.5mg, 10.88mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(4-(벤질옥시) 벤질리덴) 티아졸리딘 -2,4- 디온(5-(4-(benzyloxy)benzylidene)thiazolidine-2,4-dion)(1g,3.2mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 124의 5-(4-(벤질옥시)벤질)티아졸리딘-2,4-디온(5-(4-(benzyloxy)benzyl)thiazolidine-2,4-dione) 화합물(0.83g, 수율:82.5%)을 수득하였다. 또한, 상기 수득한 유도체 124의 화합물은 1H NMR (300 MHz, CDCl3)δ7.444(s,1H), 7.308-7.418(m,5H), 7.167(d,J=8.7Hz,2H), 6.947(d,J=8.7Hz,2H),5.052(s,2H),4.533(dd,J=3.9,3.9Hz,1H),3.487(dd,J=3.6,4.2Hz,1H),3.156(dd,J=9.0,9.6Hz,1H)이었다.In Example 120, CoCl 2 .6H 2 O was used, 4.77 mg, 0.016 mmol, dimethylglyoxime was used 74.29 mg, 0.64 mmol, and NaBH 4 was added 407.5 mg, 10.88 mmol, to prepare a mixed solution. Then, to the mixture, 5- (4- (benzyloxy) benzylidene) thiazolidine-2,4-dione (5- (4- (benzyloxy) benzylidene) thiazolidine- in THF-DMF (2: 1, 15 ml). 5- (4- (benzyloxy) benzyl) thiazolidine-2,4 of Formula 124 was carried out in the same manner, except that 2,4-dion) (1 g, 3.2 mmol) was added over 20 minutes. -Dione (5- (4- (benzyloxy) benzyl) thiazolidine-2,4-dione) compound (0.83 g, yield: 82.5%) was obtained. In addition, the obtained compound of Derivative 124 is 1 H NMR (300 MHz, CDCl 3 ) δ 7.444 (s, 1H), 7.308-7.418 (m, 5H), 7.167 (d, J = 8.7 Hz, 2H), 6.947 (d, J = 8.7 Hz, 2H), 5.052 (s, 2H), 4.533 (dd, J = 3.9, 3.9 Hz, 1H), 3.487 (dd, J = 3.6, 4.2 Hz, 1H), 3.156 (dd , J = 9.0,9.6 Hz, 1 H).
<실시예 125><Example 125>
본 발명에 따른 유도체 125의 제조Preparation of Derivative 125 According to the Invention
하기 화학식으로 나타내는 유도체 125를 다음과 같은 방법으로 제조하였다. Derivative 125 represented by the following formula was prepared in the following manner.
<유도체 125의 화학식> <Formula of derivative 125>
Figure PCTKR2009007995-appb-I000130
Figure PCTKR2009007995-appb-I000130
상기 실시예 120에서 CoCl2·6H2O을 4.17mg, 0.014mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 64.99mg, 0.56mmol 사용하였으며, NaBH4를 356.6mg, 9.52mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(3-클로로-4-(시클로헥실프로폭시) 벤질리덴) 티아졸리딘 -2,4- 디온(5-(3-chloro-4-(cyclohexylpropoxy)benzylidene)thiazolidine-2,4-dione)(1g,2.8mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 125로 표시되는 5-(3-클로로-4-(시클로헥실프로폭시)벤질)티아졸리딘-2,4-디온(5-(3-chloro-4-(cyclohexylpropoxy)benzyl)thiazolidine-2,4-dione) 화합물(0.83g, 수율:82.5%)을 수득하였다. 또한, 상기 수득한 유도체 125의 화합물은 1H NMR (300 MHz, CDCl3)δ7.891(s,1H), 7.238(s,1H), 7.072(d,J=8.4Hz,1H), 6.858(d,J=8.4Hz,1H),4.521(dd,J=3.6,3.9Hz,1H),3.807(d,J=6.3Hz,2H),3.444(dd,J=3.6,4.2Hz,1H),3.129(dd,J=9.0,9.6Hz,1H),1.693-1.917(m,6H),1.057-1.376(m,5H)이었다.In Example 120, 4.17 mg, 0.014 mmol of CoCl 2 .6H 2 O was used, 64.99 mg, 0.56 mmol of dimethylglyoxime was used, and 356.6 mg, 9.52 mmol of NaBH 4 was added to prepare a mixed solution. The mixture was then mixed with 5- (3-chloro-4- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione (5- (3-chloro) in THF-DMF (2: 1, 15 ml). 5- (3-Chloro represented by Formula 125 above by the same method except that 4- (cyclohexylpropoxy) benzylidene) thiazolidine-2,4-dione) (1 g, 2.8 mmol) was added over 20 minutes 4- (cyclohexylpropoxy) benzyl) thiazolidine-2,4-dione (5- (3-chloro-4- (cyclohexylpropoxy) benzyl) thiazolidine-2,4-dione) compound (0.83 g, yield: 82.5%). In addition, the obtained compound of Derivative 125 was 1 H NMR (300 MHz, CDCl 3 ) δ 7.891 (s, 1H), 7.238 (s, 1H), 7.072 (d, J = 8.4 Hz, 1H), 6.858 ( d, J = 8.4 Hz, 1H), 4.521 (dd, J = 3.6, 3.9 Hz, 1H), 3.807 (d, J = 6.3 Hz, 2H), 3.444 (dd, J = 3.6, 4.2 Hz, 1H), 3.129 (dd, J = 9.0, 9.6 Hz, 1H), 1.693-1.917 (m, 6H), and 1.057-1.376 (m, 5H).
<실시예 126><Example 126>
본 발명에 따른 유도체 126의 제조Preparation of Derivative 126 According to the Invention
하기 화학식으로 나타내는 유도체 126을 다음과 같은 방법으로 제조하였다. Derivative 126 represented by the following formula was prepared in the following manner.
<유도체 126의 화학식> <Formula of derivative 126>
Figure PCTKR2009007995-appb-I000131
Figure PCTKR2009007995-appb-I000131
상기 실시예 120에서 CoCl2·6H2O을 3.87mg, 0.013mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 60.35mg, 0.52mmol 사용하였으며, NaBH4를 331.1mg, 8.84mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(4-(2-티오모르폴린 1,1-디옥시드에톡시) 벤질리덴) -2,4-티아졸리딘디온(5-(4-(2-Thiomorpholine 1,1-Dioxideethoxy)benzylidene)-2,4-thiazolidinedione )(1g,2.6mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 126으로 표시되는 5-(4-(2-티오모르폴린 1,1-디옥시드에톡시) 벤질)-2,4-티아졸리딘디온(5-(4-(2-Thiomorpholine 1,1-Dioxideethoxy)benzyl)-2,4-thiazolidinedione) 화합물(0.78g, 수율:77.6%)을 수득하였다. 또한, 상기 수득한 유도체 126의 화합물은 1H NMR (300 MHz, CDCl3)δ7.728(s,1H),7.238(s,1H),7.568(d,J=9.3Hz,2H),6.893(d,J=9.3Hz,2H),4.887(dd,J=4.2,4.2Hz,1H),4.163(t,J=11.4Hz,2H),4.069(t,J=11.4Hz,2H),3.095(m,8H),2.957(m,2H)이었다.3.87mg, 0.013mmol of CoCl 2 .6H 2 O was used in Example 120, 60.35mg, 0.52mmol of dimethylglyoxime was used, and 331.1mg, 8.84mmol of NaBH 4 was added to prepare a mixed solution. Then, 5- (4- (2-thiomorpholine 1,1-dioxideethoxy) benzylidene) -2,4-thiazolidinedione (5) in THF-DMF (2: 1, 15 ml) was added to the mixed solution. Except for adding-(4- (2-Thiomorpholine 1,1-Dioxideethoxy) benzylidene) -2,4-thiazolidinedione) (1 g, 2.6 mmol) over 20 minutes, the same procedure was followed to obtain the compound of Formula 126. 5- (4- (2-thiomorpholine 1,1-dioxideethoxy) benzyl) -2,4-thiazolidinedione (5- (4- (2-Thiomorpholine 1,1-Dioxideethoxy) benzyl) -2,4-thiazolidinedione) compound (0.78 g, yield: 77.6%) was obtained. In addition, the obtained compound of derivative 126 was 1 H NMR (300 MHz, CDCl 3 ) δ7.728 (s, 1H), 7.238 (s, 1H), 7.568 (d, J = 9.3Hz, 2H), 6.893 ( d, J = 9.3 Hz, 2H), 4.887 (dd, J = 4.2, 4.2 Hz, 1H), 4.163 (t, J = 11.4 Hz, 2H), 4.069 (t, J = 11.4 Hz, 2H), 3.095 ( m, 8H), 2.957 (m, 2H).
<실시예 127><Example 127>
본 발명에 따른 유도체 127의 제조Preparation of Derivative 127 According to the Invention
하기 화학식으로 나타내는 유도체 127을 다음과 같은 방법으로 제조하였다. Derivative 127 represented by the following formula was prepared in the following manner.
<유도체 127의 화학식> <Formula of Derivative 127>
Figure PCTKR2009007995-appb-I000132
Figure PCTKR2009007995-appb-I000132
상기 실시예 120에서 CoCl2·6H2O을 4.17mg, 0.014mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 64.99mg, 0.56mmol 사용하였으며, NaBH4를 356.6mg, 9.52mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(2-클로로-4-(2-시클로헥실에톡시) 벤질리덴) 티아졸리딘 -2,4- 디온(5-(2-chloro-4-(2-cyclohexylethoxy)benzylidene)thiazolidine-2,4-dione)(1g, 2.7mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 127으로 표시되는 5-(2-클로로-4-(2-시클로헥실에톡시)벤질)티아졸리딘-2,4-디온(5-(2-chloro-4-(2-cyclohexylethoxy)benzyl)thiazolidine-2,4-dione) 화합물(0.82g, 수율:81.6%)을 수득하였다. 또한, 상기 수득한 유도체 127의 화합물은 1H NMR (300 MHz, CDCl3)δ7.891(s,1H), 7.249(s,1H), 7.106(d,J=8.7Hz,1H), 6.958(d,J=8.7Hz,1H),4.531(dd,J=3.6,3.9Hz,1H),3.917(t,J=6.6Hz,2H),3.354(dd,J=3.6,4.2Hz,1H),3.239(dd,J=9.0,9.6Hz,1H),2.062-2.149(m,2H),1.793-1.827(m,6H),1.052-1.216(m,5H)이었다.In Example 120, 4.17 mg, 0.014 mmol of CoCl 2 .6H 2 O was used, 64.99 mg, 0.56 mmol of dimethylglyoxime was used, and 356.6 mg, 9.52 mmol of NaBH 4 was added to prepare a mixed solution. Then, to the mixed solution, 5- (2-chloro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (5- (2) in THF-DMF (2: 1, 15 ml). 5-chloro-4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (1g, 2.7mmol) was added over 20 minutes to carry out the same method as the formula (127). (2-chloro-4- (2-cyclohexylethoxy) benzyl) thiazolidine-2,4-dione (5- (2-chloro-4- (2-cyclohexylethoxy) benzyl) thiazolidine-2,4-dione ) (0.82 g, yield: 81.6%) was obtained. In addition, the obtained compound of the derivative 127 was 1 H NMR (300 MHz, CDCl 3 ) δ 7.891 (s, 1H), 7.249 (s, 1H), 7.106 (d, J = 8.7 Hz, 1H), 6.958 ( d, J = 8.7 Hz, 1H), 4.531 (dd, J = 3.6, 3.9 Hz, 1H), 3.917 (t, J = 6.6 Hz, 2H), 3.354 (dd, J = 3.6, 4.2 Hz, 1H), 3.239 (dd, J = 9.0, 9.6 Hz, 1H), 2.062-2.149 (m, 2H), 1.793-1.827 (m, 6H), and 1.052-1.216 (m, 5H).
<실시예 128><Example 128>
본 발명에 따른 유도체 128의 제조Preparation of Derivative 128 According to the Invention
하기 화학식으로 나타내는 유도체 128을 다음과 같은 방법으로 제조하였다. Derivative 128 represented by the following formula was prepared in the following manner.
<유도체 128의 화학식> <Formula of derivative 128>
Figure PCTKR2009007995-appb-I000133
Figure PCTKR2009007995-appb-I000133
상기 실시예 120에서 CoCl2·6H2O을 4.17mg, 0.014mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 64.99mg, 0.56mmol 사용하였으며, NaBH4를 356.6mg, 9.52mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(4-(2-시클로헥실프로폭시)-3-메틸벤질리덴) 티아졸리딘 -2,4- 디온(5-(4-(2-cyclohexylpropoxy)-3-methylbenzylidene)thiazolidine-2,4-dione)(1g, 2.8mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 128으로 표시되는 5-(4-(2-시클로헥실프로폭시)-3-메틸벤질)티아졸리딘-2,4-디온(5-(4-(2-cyclohexylpropoxy)-3-methylbenzyl)thiazolidine-2,4-dione) 화합물(0.80g, 수율:79.8%)을 수득하였다. 또한, 상기 수득한 유도체 128의 화합물은 1H NMR (300 MHz, CDCl3)δ7.902(s,1H), 7.346(s,1H), 7.144(d,J=8.7Hz,1H), 7.016(d,J=8.7Hz,1H),4.643(dd,J=3.9,3.9Hz,1H),4.368(t,J=13.5Hz,2H),3.542(dd,J=4.2,4.2Hz,1H),3.164(dd,J=9.6,9.6Hz,1H),2.186(s,3H),1.588-1.653(m,6H),1.486-1.528(m,2H),1.262-1.318(m,4H),0.748-0.877(m,3H)이었다.In Example 120, 4.17 mg, 0.014 mmol of CoCl 2 .6H 2 O was used, 64.99 mg, 0.56 mmol of dimethylglyoxime was used, and 356.6 mg, 9.52 mmol of NaBH 4 was added to prepare a mixed solution. Then, to the mixed solution, 5- (4- (2-cyclohexylpropoxy) -3-methylbenzylidene) thiazolidine-2,4-dione (5- (4) in THF-DMF (2: 1, 15 ml). Except that-(2-cyclohexylpropoxy) -3-methylbenzylidene) thiazolidine-2,4-dione) (1 g, 2.8 mmol) was added over 20 minutes, the same procedure was followed to yield 5- ( 4- (2-cyclohexylpropoxy) -3-methylbenzyl) thiazolidine-2,4-dione (5- (4- (2-cyclohexylpropoxy) -3-methylbenzyl) thiazolidine-2,4-dione) compound (0.80 g, yield: 79.8%) was obtained. In addition, the obtained compound of derivative 128 was 1 H NMR (300 MHz, CDCl 3 ) δ7.902 (s, 1H), 7.346 (s, 1H), 7.144 (d, J = 8.7Hz, 1H), 7.016 ( d, J = 8.7 Hz, 1H), 4.643 (dd, J = 3.9, 3.9 Hz, 1H), 4.368 (t, J = 13.5 Hz, 2H), 3.542 (dd, J = 4.2, 4.2 Hz, 1H), 3.164 (dd, J = 9.6,9.6Hz, 1H), 2.186 (s, 3H), 1.588-1.653 (m, 6H), 1.486-1.528 (m, 2H), 1.262-1.318 (m, 4H), 0.748- 0.877 (m, 3 H).
<실시예 129><Example 129>
본 발명에 따른 유도체 129의 제조Preparation of Derivative 129 According to the Invention
하기 화학식으로 나타내는 유도체 129를 다음과 같은 방법으로 제조하였다. Derivative 129 represented by the following formula was prepared in the following manner.
<유도체 129의 화학식> <Formula of derivative 129>
Figure PCTKR2009007995-appb-I000134
Figure PCTKR2009007995-appb-I000134
상기 실시예 120에서 CoCl2·6H2O을 3.87mg, 0.013mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 60.35mg, 0.52mmol 사용하였으며, NaBH4를 331.1mg, 8.84mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(4-(비페닐-4-일메톡시)벤질리덴) 티아졸리딘 -2,4- 디온(5-(4-(biphenyl-4-ylmethoxy)benzylidene)thiazolidine-2,4-dione)(1g,2.6mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 129로 표시되는 5-(4-(비페닐-4-일메톡시)벤질) 티아졸리딘 -2,4- 디온5-(4-(biphenyl-4-ylmethoxy)benzyl)thiazolidine-2,4-dione 화합물(0.81g, 수율:80.5%)을 수득하였다. 또한, 상기 수득한 유도체 129의 화합물은 1H NMR (300 MHz, CDCl3)δ7.727(s,1H), 7.661-7.703(m,4H), 7.435-7.578(m,4H), 7.205-7.359(m,1H),7.205(d,J=8.7Hz,2H),6.952(d,J=8.7Hz,2H),5.112(s,2H),4.894(dd,J=4.2,4.2Hz,1H),3.381(dd,J=4.2,4.2Hz,1H),3.089(dd,J=8.7,9.3Hz,1H) 이었다.3.87mg, 0.013mmol of CoCl 2 .6H 2 O was used in Example 120, 60.35mg, 0.52mmol of dimethylglyoxime was used, and 331.1mg, 8.84mmol of NaBH 4 was added to prepare a mixed solution. Then, to the mixed solution, 5- (4- (biphenyl-4-ylmethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (biphenyl) in THF-DMF (2: 1, 15 ml). The same procedure was followed for the addition of 4-ylmethoxy) benzylidene) thiazolidine-2,4-dione) (1 g, 2.6 mmol) over 20 minutes, to obtain 5- (4- (non- Phenyl-4-ylmethoxy) benzyl) thiazolidine-2,4-dione5- (4- (biphenyl-4-ylmethoxy) benzyl) thiazolidine-2,4-dione compound (0.81 g, yield: 80.5%) Obtained. In addition, the compound of Derivative 129 obtained was 1 H NMR (300 MHz, CDCl 3 ) δ7.727 (s, 1H), 7.661-7.703 (m, 4H), 7.435-7.578 (m, 4H), 7.205-7.359 (m, 1H), 7.205 (d, J = 8.7Hz, 2H), 6.952 (d, J = 8.7Hz, 2H), 5.112 (s, 2H), 4.894 (dd, J = 4.2,4.2Hz, 1H) , 3.381 (dd, J = 4.2, 4.2 Hz, 1H), 3.089 (dd, J = 8.7, 9.3 Hz, 1H).
<실시예 130><Example 130>
본 발명에 따른 유도체 130의 제조Preparation of Derivative 130 According to the Invention
하기 화학식으로 나타내는 유도체 130을 다음과 같은 방법으로 제조하였다. Derivative 130 represented by the following formula was prepared in the following manner.
<유도체 130의 화학식> <Formula of derivative 130>
Figure PCTKR2009007995-appb-I000135
Figure PCTKR2009007995-appb-I000135
상기 실시예 120에서 CoCl2·6H2O을 4.77mg, 0.016mmol 사용하였고, 디메틸글리옥심(dimethylglyoxime)을 74.29mg, 0.64mmol 사용하였으며, NaBH4를 407.5mg, 10.88mmol를 첨가하여 혼합액을 제조한 후, 상기 혼합액에 THF-DMF (2:1, 15ml) 중의 5-(4-(2-시클로펜틸에톡시)벤질리덴) 티아졸리딘 -2,4- 디온(5-(4-(2-cyclopentylethoxy)benzylidene)thiazolidine-2,4-dione)(1g,3.2mmol)을 20분에 걸쳐 첨가한 것을 제외하고는 동일한 방법을 수행하여 상기 화학식 130으로 표시되는 5-(4-(2-시클로펜틸에톡시)벤질) 티아졸리딘 -2,4- 디온(5-(4-(2-cyclopentylethoxy)benzyl)thiazolidine-2,4-dione) 화합물(0.82g, 수율:81.6%)을 수득하였다. 또한, 상기 수득한 유도체 130의 화합물은 1H NMR (300 MHz, CDCl3)δ7.926(s,1H), 7.148(d,J=8.4Hz,2H), 6.86(d,J=8.4Hz,2H), 4.529(dd,J=3.6,4.2Hz,1H),3.98(t,J=13.5Hz,2H),3.485(dd,J=3.9,3.9Hz,1H),3.143(dd,J=9.6,9.3Hz,1H),1.810-1.845(m,1H),1.764-1.787(m,4H),1.510-1.623(m,4H),1.125-1.192(m,2H) 이었다.In Example 120, CoCl 2 .6H 2 O was used, 4.77 mg, 0.016 mmol, dimethylglyoxime was used 74.29 mg, 0.64 mmol, and NaBH 4 was added 407.5 mg, 10.88 mmol, to prepare a mixed solution. Then, to the mixed solution, 5- (4- (2-cyclopentylethoxy) benzylidene) thiazolidine-2,4-dione (5- (4- (2-) in THF-DMF (2: 1, 15 ml). 5- (4- (2-cyclopentyl) represented by Chemical Formula 130 by following the same method except that cyclopentylethoxy) benzylidene) thiazolidine-2,4-dione) (1 g, 3.2 mmol) was added over 20 minutes Ethoxy) benzyl) thiazolidine-2,4-dione (5- (4- (2-cyclopentylethoxy) benzyl) thiazolidine-2,4-dione) compound (0.82 g, yield: 81.6%) was obtained. In addition, the compound of Derivative 130 obtained was 1 H NMR (300 MHz, CDCl 3 ) δ7.926 (s, 1H), 7.148 (d, J = 8.4Hz, 2H), 6.86 (d, J = 8.4Hz, 2H), 4.529 (dd, J = 3.6, 4.2 Hz, 1H), 3.98 (t, J = 13.5 Hz, 2H), 3.485 (dd, J = 3.9, 3.9 Hz, 1H), 3.143 (dd, J = 9.6) , 9.3 Hz, 1H), 1.810-1.845 (m, 1H), 1.764-1.787 (m, 4H), 1.510-1.623 (m, 4H), and 1.125-1.192 (m, 2H).
<실험예 1>Experimental Example 1
본 발명에 따른 유도체 화합물들의 15-PGDH에 대한 억제 활성 분석 Inhibitory activity analysis of 15-PGDH of derivative compounds according to the present invention
<1-1> 15-PGDH의 발현 및 정제<1-1> Expression and Purification of 15-PGDH
상기 실시예 1 내지 130에서 합성된 유도체들의 15-PGDH 억제능을 확인하기 위하여 먼저 하기와 같은 방법으로 15-PGDH를 정제하였다. pGEX-2T 발현 벡터의 BamHI 및 EcoRI 제한효소 사이트를 포함하는 15-PGDH cDNA 플라스미드를 대장균 BL-21 LysS에 당업계에서 사용되는 일반적인 방법을 사용하여 형질전환 하였다. 이후 상기 형질전환된 세포를 50μg/ml 암피실린을 함유한 LB 배지에서(500ml) 37℃의 온도 및 220rpm의 속도로 교반하면서 OD600이 0.6이 될 때까지 배양하였다. 이후 이소프로필 베타-D-티오갈락톡시드(1mM)를 첨가하였고 세포를 다시 25℃에서 12시간 동안 배양하였다. 그런 뒤, 세포들을 4℃에서 4000g의 속도로 30분간 원심분리하여 펠렛을 모았다. 상기 세포 펠렛을 20ml의 세포 용해 버퍼[1 x PBS 버퍼(pH 7.4):1mM EDTA 및 0.1mM DTT함유]로 용해한 뒤, 4℃에서 14 x 10s 초음파처리 하였다. 분해된 세포들은 4℃에서 20분 동안 4000g의 속도로 원심분리 하였다. 이후 상층액을 세포 용해 버퍼[1 x PBS 버퍼(pH 7.4), 1mM EDTA 및 0.1mM DTT함유]로 4℃에서 평형화시킨 글루타치온-세파로즈 4B 컬럼에 천천히 로딩하였다. 용해 버퍼를 이용하여 OD280이 0.005 이하가 될 때까지 세척하였다. 그런 뒤, 상온에서 5분 동안 용출 버퍼[50mM Tris-HCl(pH 8.0), 10mM 환원된 글루타치온, 1mM EDTA 및 0.1mM DTT함유]를 이용하여 글루타치온-세파로즈 4B 컬럼으로부터 15-PGDH를 용출시켰다. 정제된 상기 효소의 농도 측정 및 정제도는 SDS-PAGE를 통해 확인하였다.In order to confirm the inhibitory ability of 15-PGDH of the derivatives synthesized in Examples 1 to 130, first, 15-PGDH was purified. The 15-PGDH cDNA plasmid containing the BamHI and EcoRI restriction enzyme sites of the pGEX-2T expression vector was transformed into E. coli BL-21 LysS using the conventional methods used in the art. The transformed cells were then incubated in LB medium containing 50 μg / ml ampicillin (500 ml) at a temperature of 37 ° C. and a speed of 220 rpm until OD 600 became 0.6. Isopropyl beta-D-thiogalactoxide (1 mM) was then added and the cells were incubated again at 25 ° C. for 12 hours. Cells were then centrifuged at 4 ° C. at 4000g for 30 minutes to collect pellets. The cell pellet was lysed with 20 ml of cell lysis buffer [containing 1 × PBS buffer (pH 7.4): 1 mM EDTA and 0.1 mM DTT] and sonicated at 4 ° C. at 14 × 10 s. The digested cells were centrifuged at 4000g for 20 minutes at 4 ° C. The supernatant was then slowly loaded into a Glutathione-Sepharose 4B column equilibrated at 4 ° C. with cell lysis buffer [containing 1 × PBS buffer (pH 7.4), 1 mM EDTA and 0.1 mM DTT. The lysis buffer was used to wash the OD 280 up to 0.005. Then 15-PGDH was eluted from the Glutathione-Sepharose 4B column using elution buffer (containing 50 mM Tris-HCl, pH 8.0), 10 mM reduced glutathione, 1 mM EDTA and 0.1 mM DTT at room temperature for 5 minutes. Concentration measurement and purity of the purified enzyme were confirmed by SDS-PAGE.
<1-2> 15-PGDH 억제제의 활성 측정<1-2> Determination of Activity of 15-PGDH Inhibitor
본 발명에 따른 유도체 화합물들이 15-PGDH를 억제하는 효과가 있는지를 확인하기 위하여, 상기 실험예 <1-1>에서 정제한 15-PGDH를 상기 실시예 1 내지 130에서 합성된 본 발명의 유도체 화합물들이 억제할 수 있는지를 340nm에서 형성된 NADH를 형광 스펙트라포토미터로 측정함으로써 수행하였다. 즉, 세포에 대하여 50mM Tris-HCl(pH 7.5), 0.1mM DTT, 0.25 mM(NAD+), 10ug의 정제된 15-PGDH 효소, 21μM PGE2 및 다양한 농도(0.0001μM 내지 64μM)의 본 발명의 유도체 화합물을 포함한 총 부피가 2ml인 용액을 첨가하였다. 이후, 반응 혼합물의 흡광도를 340nm에서 기록하였고, 15-PGDH의 억제제인 본 발명의 유도체 화합물들의 활성은 340nm에서 준비된 다양한 농도에 따른 NADH 흡광도의 평균값을 표준 곡선으로부터 측정하였다. 본 발명에 따른 유도체 화합물들의 15-PGDH의 억제 활성 결과는 하기 표 1에 기재된 바와 같으며, 하기 표 1에서 IC50은 본 발명에 따른 유도체 화합물이 15-PGDH 활성의 50%를 저해하는 농도를 나타낸 것이다. In order to confirm whether the derivative compounds according to the present invention have an effect of inhibiting 15-PGDH, the derivative compounds of the present invention synthesized 15-PGDH purified in Experimental Example <1-1> in Examples 1 to 130 It was carried out by measuring the NADH formed at 340nm by fluorescence spectrophotometer to see if they could be suppressed. That is, 50 mM Tris-HCl (pH 7.5), 0.1 mM DTT, 0.25 mM (NAD + ), 10 ug of purified 15-PGDH enzyme, 21 μM PGE 2 and various concentrations (0.0001 μM to 64 μM) to cells A solution of 2 ml total volume containing the derivative compound was added. The absorbance of the reaction mixture was then recorded at 340 nm, and the activity of the derivative compounds of the present invention, inhibitors of 15-PGDH, was determined from standard curves with the average value of NADH absorbance at various concentrations prepared at 340 nm. The inhibitory activity results of 15-PGDH of the derivative compounds according to the present invention are as shown in Table 1 below, IC 50 in Table 1 indicates the concentration at which the derivative compound according to the present invention inhibits 50% of 15-PGDH activity It is shown.
그 결과, 하기 표 1에 기재된 바와 같이 본 발명에 따른 신규한 티아졸리딘디온 유도체 화합물들 모두는 15-PGDH를 억제하는 활성이 있는 것을 확인할 수 있었으며, 특히 티아졸리딘의 5에 연결된 벤질리덴(benzylidene)의 R1이 할로겐일 경우 15-PGDH의 억제활성이 현저히 우수한 것으로 나타났다. As a result, as shown in Table 1, all of the novel thiazolidinedione derivative compounds according to the present invention was found to have an activity of inhibiting 15-PGDH, in particular benzylidene linked to 5 of thiazolidine ( Benzylidene) showed that the inhibitory activity of 15-PGDH was remarkably excellent when R 1 was halogen.
<표 1>TABLE 1
[규칙 제91조에 의한 정정 31.03.2010]　
Figure WO-DOC-FIGURE-1
[Revision 31.03.2010 under Rule 91]
Figure WO-DOC-FIGURE-1
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Figure WO-DOC-FIGURE-2
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Figure WO-DOC-FIGURE-2
[규칙 제91조에 의한 정정 31.03.2010]　
Figure WO-DOC-FIGURE-3
[Revision 31.03.2010 under Rule 91]
Figure WO-DOC-FIGURE-3
[규칙 제91조에 의한 정정 31.03.2010]　
Figure WO-DOC-FIGURE-4
[Revision 31.03.2010 under Rule 91]
Figure WO-DOC-FIGURE-4
[규칙 제91조에 의한 정정 31.03.2010]　
Figure WO-DOC-FIGURE-5
[Revision 31.03.2010 under Rule 91]
Figure WO-DOC-FIGURE-5
[규칙 제91조에 의한 정정 31.03.2010]　
Figure WO-DOC-FIGURE-6
[Revision 31.03.2010 under Rule 91]
Figure WO-DOC-FIGURE-6
[규칙 제91조에 의한 정정 31.03.2010]　
Figure WO-DOC-FIGURE-7
[Revision 31.03.2010 under Rule 91]
Figure WO-DOC-FIGURE-7
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (11)

  1. 하기 화학식으로 표시되는 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염: Thiazolidinedione derivative represented by the following formula or a pharmaceutically acceptable salt thereof:
    Figure PCTKR2009007995-appb-I000143
    Figure PCTKR2009007995-appb-I000143
    상기 식에서, A 및 A' 는 각각 독립적으로 O 또는 S 이고, Wherein A and A 'are each independently O or S,
    R1은 수소 또는 CH2CH2OH 이며,R 1 is hydrogen or CH 2 CH 2 OH,
    R2, R3, R4 및 R5는 각각 독립적으로 수소, 니트로기, 아민, 알콕시, 알킬, 트리플루오로메틸, 카르복실, 할로겐 또는
    Figure PCTKR2009007995-appb-I000144
    이고,    R 2 , R 3 , R 4 and R 5 are each independently hydrogen, nitro group, amine, alkoxy, alkyl, trifluoromethyl, carboxyl, halogen or
    Figure PCTKR2009007995-appb-I000144
    ego,
    이때 상기
    Figure PCTKR2009007995-appb-I000145
    는 벤젠고리의 3번 또는 4번 탄소 위치에서 결합하며,     At this time
    Figure PCTKR2009007995-appb-I000145
    Is bonded at the 3 or 4 carbon position of the benzene ring,
    R6는 수소, 알킬, 치환 또는 비치환 (헤테로)사이클로알킬, (헤테로)사이클로알케닐 또는 (헤테로)아릴로 이루어진 군 중에서 선택되며, 점선은 단일 또는 이중결합을 나타낸 것이고, n은 0 내지 5의 정수이다.R 6 is selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted (hetero) cycloalkyl, (hetero) cycloalkenyl, or (hetero) aryl, the dotted line represents a single or double bond, n is from 0 to 5 Is an integer.
  2. 제1항에 있어서, 상기 R3가
    Figure PCTKR2009007995-appb-I000146
    일 경우, R2, R4 및 R5는 각각     The compound of claim 1, wherein R 3 is
    Figure PCTKR2009007995-appb-I000146
    , R 2 , R 4 and R 5 are each
    독립적으로 H, NO2, NH2, CH3, Cl, Br, F, COOH, CF3, CH3O, CH3CH2O로 이루어진 군 중에서 선택되고, 상기 R4가
    Figure PCTKR2009007995-appb-I000147
    일 경우, R2, R3 및 R5는 각각 독립적으로 H, NO2, NH2, CH3, Cl, Br, F, COOH, CF3, CH3O, CH3CH2O로 이루어진 군 중에서 선택되는 것을 특징으로 하는 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염.    Independently H, NO 2 , NH 2 , CH 3 , Cl, Br, F, COOH, CF 3 , CH 3 O, CH 3 CH 2 O, wherein R4 is
    Figure PCTKR2009007995-appb-I000147
    In the case, R 2 , R 3 and R 5 are each independently H, NO 2 , NH 2 , CH 3 , Cl, Br, F, COOH, CF 3 , CH 3 O, CH 3 CH 2 O Thiazolidinedione derivative or a pharmaceutically acceptable salt thereof, which is selected.
  3. 제1항에 있어서, 하기 표의 화학식으로 표시되는 유도체 1 내지 유도체 130으로 이루어진 군중에서 선택되는 것을 특징으로 하는 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염.The thiazolidinedione derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the thiazolidinedione derivative is selected from the group consisting of derivatives 1 to 130 represented by the formula of the following table.
    Figure PCTKR2009007995-appb-I000148
    Figure PCTKR2009007995-appb-I000148
    Figure PCTKR2009007995-appb-I000149
    Figure PCTKR2009007995-appb-I000149
    Figure PCTKR2009007995-appb-I000150
    Figure PCTKR2009007995-appb-I000150
    Figure PCTKR2009007995-appb-I000151
    Figure PCTKR2009007995-appb-I000151
  4. 제1항 내지 제3항 중 어느 한 항에 따른 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 탈모방지 및 발모촉진용 약학적 조성물.  A pharmaceutical composition for preventing hair loss and promoting hair growth, comprising a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 제1항 내지 제3항 중 어느 한 항에 따른 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 심혈관계 질환의 예방 및 치료용 약학적 조성물. A pharmaceutical composition for the prevention and treatment of cardiovascular diseases comprising a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  6. 제5항에 있어서, 상기 심혈관계 질환은 고혈압, 동맥경화, 협심증, 고지혈증, 심근경색 및 심부전으로 이루어진 군중에서 선택되는 것을 특징으로 하는 심혈관계 질환의 약학적 조성물.  6. The pharmaceutical composition of cardiovascular diseases according to claim 5, wherein the cardiovascular disease is selected from the group consisting of hypertension, arteriosclerosis, angina pectoris, hyperlipidemia, myocardial infarction and heart failure.
  7. 제1항 내지 제3항 중 어느 한 항에 따른 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 위장질환의 예방 및 치료용 약학적 조성물.  A pharmaceutical composition for the prevention and treatment of gastrointestinal diseases, which contains a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  8. 제7항에 있어서, 상기 위장질환은 위염 또는 위궤양인 것을 특징으로 하는 위장질환의 예방 및 치료용 약학적 조성물.  According to claim 7, wherein the gastrointestinal disease is gastritis or gastric ulcer pharmaceutical composition for the prevention and treatment of gastrointestinal diseases.
  9. 제1항 내지 제3항 중 어느 한 항에 따른 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 신장질환의 예방 및 치료용 약학적 조성물.  A pharmaceutical composition for the prophylaxis and treatment of kidney disease, comprising a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  10. 제1항 내지 제3항 중 어느 한 항에 따른 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 골형성용 조성물.  A composition for bone formation comprising thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  11. 제1항 내지 제3항 중 어느 한 항에 따른 티아졸리딘디온(thiazolidinedione) 유도체 또는 그의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 화상 치료용 조성물.  A composition for treating burns comprising a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
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